TW202228772A - Pancreatic cancer quadruplet therapeutic agent combining atezolizumab, tocilizumab, gemcitabine, and nab-paclitaxel - Google Patents

Abstract

This disclosure relates to a drug, treatment method, kit, and use, for treating pancreatic cancer in an individual by combining a PD-1/PD-L1 signal inhibitor, an IL-6 inhibitor, and at least one other antitumor agent.

Description

Pancreatic cancer therapeutic agent by concomitant use of 4 doses of atezolizumab, tocilizumab, gemcitabine, and nab-paclitaxel

The present invention relates to a method characterized by the administration of an IL-6 signaling inhibitor (more specifically tocilizumab), gemcitabine, nab-paclitaxel, and a PD-1/PD-L1 signaling inhibitor (more specifically ati Medicines, methods of treatment, kits, uses for treating pancreatic cancer in an individual. More specifically, the present invention relates to a medicament, method of treatment, kit, treatment for pancreatic cancer in an individual characterized by the administration of tocilizumab, gemcitabine, nab-paclitaxel, and atezolizumab. use.

Pancreatic cancer is a refractory cancer with a 5-year survival rate of only 7%. The number of pancreatic cancer deaths and patients in Japan were 31,831 and 37,233, respectively (2015). ). Epithelial tumors and non-epithelial tumors exist in pancreatic cancer, and epithelial tumors are roughly divided into exocrine tumors and endocrine tumors. Exocrine tumors are classified into serous cystic tumors, mucinous cystic tumors, intraductal papillary mucinous tumors of the pancreas, invasive pancreatic ductal carcinoma, and acinar cell tumors. According to the National Registration Survey Report of Pancreatic Cancer, invasive pancreatic ductal carcinoma accounts for about 90% of all pancreatic cancer patients, and tubular adenocarcinoma has the highest frequency (Non-Patent Document 8).

Surgical resection is the only treatment that can be expected to cure pancreatic cancer, but it is generally believed that pancreatic cancer can be removed in the first and second stages. However, the resection rate is as low as 10%-20%, and most patients are unresectable advanced cases at the time of discovery. Even if they can be successfully resected, the recurrence rate is as high as 80%, and the prognosis is extremely poor (Non-Patent Document 9).

In the 2019 edition of the guidelines for the diagnosis and treatment of pancreatic cancer, the recommended regimens for primary chemotherapy for unresectable pancreatic cancer vary according to the tumor status (Non-Patent Document 10). For distant metastatic pancreatic cancer, FOLFIRINOX therapy (5-FU, irinotecan, oxaliplatin, levofolinate) or GN therapy (gemcitabine hydrochloride (GEM), nab-paclitaxel) is recommended. Depending on the patient's status, GEM single-dose therapy, GEM+erlotinib hydrochloride combination therapy, S-1 single-agent therapy, or GEM+S-1 combination therapy should be considered. For locally advanced pancreatic cancer, chemotherapy alone or chemo-radiation therapy has become common in clinical practice, and the usefulness of FOLFIRINOX therapy or GN therapy is expected.

The development after the second treatment is also in progress, and it was reported in a phase III trial (NAPOLI-1) in patients with metastatic pancreatic cancer with a history of GEM therapy, and the nanoliposome formulation of irinotecan MM was used. -398 and 5-FU・Leucovorin therapy. The overall survival (OS), which was the main evaluation item in the combined therapy of 5-FU and folinic acid, was 4.2 months, while it was extended to 6.1 months by adding the nanoliposome preparation of irinotecan [risk]. ratio (HR) 0.67, 95% confidence interval 0.49-0.92 (p=0.012)], a statistically significant improvement (Non-Patent Document 11), and it was also approved in Japan in 2020. In the guidelines, a 5-FU-related regimen containing a combination therapy of 5-FU, folinic acid, and irinotecan nanoliposome preparations was proposed after the GEM-related regimen, and a single dose of GEM was proposed after the 5-FU-related regimen. GEM-related regimens of therapy or GN therapy.

One of the characteristics of refractory cancers represented by pancreatic cancer is that the amount of stroma is very large compared to the amount of cancer cells, and a large number of fibroblasts are proliferated in the stroma. Fibrosis, one of the characteristics of the pancreatic cancer microenvironment, is called desmoplasia. Inhibition of connective tissue hyperplasia improves the penetration of drugs into tumors, etc., and enhances the effect of existing anticancer agents (Non-Patent Document 13), so it is expected to be a novel therapeutic concept. On the other hand, regarding the therapeutic policy of pancreatic cancer targeting hyaluronic acid (HA), a fibrous interstitial component, in the hyaluronic acid dissolving agent for metastatic pancreatic ductal adenocarcinoma (PEGylated recombinant human transparent Ronidase (PEGPH20: pegylated recombinant human hyaluronidase) and gemcitabine + nab-paclitaxel (GEM + nab-PTX) + PEGPH20 therapy (PAG therapy) as standard treatment drugs showed the expected results in the randomized phase II trial, and also showed that hyaluronic acid The expression status can be a biomarker (HALO 109-202 test, Non-Patent Document 12). However, the results of the phase III trial (HALO 109-301 trial) of PAG therapy for metastatic pancreatic ductal adenocarcinoma with high HA expression did not improve compared with nab-PTX+GEM (AG therapy). Inhibition of connective tissue hyperplasia does not increase the effect of the current treatment (Non-Patent Document 3).

On the other hand, methods of not directly targeting hyaluronic acid but affecting the surrounding environment of cancer cells to enhance the effect of chemotherapy have also been reported. Regarding the mechanism of action of the combination therapy of nab-paclitaxel and gemcitabine (GEM), it was revealed that in a mouse xenograft model of pancreatic cancer, changes in the tumor microenvironment resulted in enhanced delivery of GEM into the tumor (patent Reference 1). In addition, when metformin is administered as a drug for diabetes treatment, regardless of the effect on cancer cells or tumor metabolism itself, the tumor microenvironment will be changed, and the drug (anti-cancer agent or anti-fibrotic agent) will be promoted to reach the target. , and reduce connective tissue hyperplasia (Patent Document 5).

Tocilizumab (Actemra ^{( registered trademark )} , TCZ, CAS number: 375823-41-9) is a humanized anti-human IL-6 receptor (IL-6R) monoclonal antibody of IgG1 subtype developed in Japan ( Non-patent document 14). The above-mentioned tocilizumab is a mouse-type human IL-6R monoclonal antibody by gene recombination technology, especially the complementarity determining region (CDR) with high affinity to the antigen in the variable region, and the other parts are set as the mouse-type human IL-6R monoclonal antibody. Human IgG1, and created using Chinese Hamster Ovary (CHO) cells. Tocilizumab exhibits efficacy by inhibiting the biological effects of IL-6 by specifically binding to both soluble IL-6R and membrane-bound IL-6R. In Japan, Actemra ^{( registered trademark )} intravenous injection 200, which is an anti-IL-6 receptor monoclonal antibody, was approved for Castleman's disease in April 2005, and was additionally approved for rheumatoid arthritis in April 2008. Arthritis, polyarticular active juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis were additionally approved for Takayasu arteritis and giant cell arteritis in August 2017, and development work has been ongoing since then. continue.

On the other hand, regarding the administration of tocilizumab to pancreatic cancer patients, 15 patients with advanced pancreatic cancer before initial treatment with a CRP (C-reactive protein, C-reactive protein) of 2.0 mg/dL or more were used as Subjects, a multicenter, open-label, phase I/II trial of TCZ+GEM combination therapy was performed. Regarding the administration method, only planned administration of TCZ 8 mg/kg (Day1, Day15) + GEM 1000 mg/m2 (Day1, Day8, Day15), no DLT (dose-limiting toxicity, dose-limiting toxicity), major adverse events Thrombocytopenia (grade 3 and above: 40%) and neutropenia (grade 3 and above: 33%). Survival was 1.6 months for the cohort of patients with a CRP of 10.6 mg/dL or higher (8) compared to 5.8 months for the cohort of patients with a CRP of 2.0 mg/dL or higher and less than 10.6 mg/dL. The patient group with a CRP of 10.6 mg/dL or more was judged to be difficult to continue the test and was discontinued (Non-Patent Document 15, Patent Document 2). Furthermore, regarding the combined use of tocilizumab administration with gemcitabine and nab-paclitaxel therapy, although a clinical trial protocol has been disclosed, no treatment results have been reported so far (Non-Patent Documents 4 and 5).

Inflammation mediated by JAK/STAT signaling is one of the causes of chemotherapeutic resistance in cancer. The JAK/STAT3 pathway is activated by the stimulation of multiple cytokines or growth factors represented by the IL-6 family. In mice, the use of an anti-IL-6R antibody to block IL-6 receptors inhibits STAT3 activation, resulting in enhanced efficacy of chemotherapy for pancreatic ductal adenocarcinoma (Non-Patent Document 2).

PD-1/PD-L1 signaling inhibitors are used as immune checkpoint inhibitors to treat various cancers. Currently available, nivolumab (Opdivo ^{( registered trademark )} ) and pembrolizumab (Keytruda ⁽ registered ^{trademark )} ) as anti-PD-1 antibodies, or as anti-PD-L1 antibodies are known Valulumab (Imfinzi ^{( registered trademark )} ), atezolizumab (Tecentriq ^{( registered trademark )} , CAS number: 1380723-44-3), and avelumab (Bavencio ^{( registered trademark )} ) and the like.

Atezolizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting programmed death ligand 1 (PD-L1). It is believed that atezolizumab binds to PD-L1, inhibits the interaction between PD-L1 and PD-1 and between PD-L1 and B7-1, and promotes the reactivation of T cells, thereby producing an anti-tumor effect. In Japan, in April 2018, it was sold with "unresectable advanced, recurrent non-small cell lung cancer" as efficacy and effect, and in December of the same year, it was additionally approved for "squamous cell carcinoma that has not been treated with chemotherapy". Unresectable advanced and recurrent non-small cell lung cancer" usage and dosage. In addition, it was approved for "advanced small cell lung cancer" in August 2019. Also, in September 2019, it was approved for expanded use in breast cancer (PD-L1 positive triple-negative breast cancer (TNBC)), and in September 2020, the combination therapy with Avastin was additionally approved for unresectable treatment. Hepatocellular carcinoma (HCC: hepatocellular carcinoma).

There are many proposals and reports on the combination of PD-1/PD-L1 signaling inhibitors and other agents to obtain anti-tumor effects. For example, the combined use of an anti-PD-L1 antibody and gemcitabine has been proposed (Patent Document 3). Complete remission was achieved in a phase I clinical trial by using an anti-PD-L1 antibody in combination with nab-PTX and carboplatin in patients with non-small cell lung cancer (Patent Document 4). In a mouse model, it has been suggested that it is possible to treat pancreatic cancer by using an anti-IL-6 antibody in combination with an anti-PD-L1 antibody (Non-Patent Document 1). However, in a phase I trial of advanced pancreatic cancer, the combined effect of the anti-PD-1 antibody nivolumab + nab-PTX + gemcitabine was comparable to that of nab-PTX + gemcitabine (Non-Patent Document 6).

The following data were obtained in clinical trials of advanced triple-negative breast cancer and advanced NSCLC that did not respond to platinum-containing regimens. According to the data, the increased expression of PD-L1 in tumor tissue can help enhance immune checkpoint inhibitors. Effects of tislizumab (Non-Patent Documents 16 and 17). [Prior Art Literature] [Patent Literature]

[Patent Document 1] Japanese Patent No. 6242213/WO2011123393/Japanese Patent Publication No. 2013-523743/US20120076862 [Patent Document 2] Japanese Patent No. 5904552/WO2011149046/US20130149302 [Patent Document 3] Japanese Patent No. 5681638/WO2010077634/Japanese Patent Publication No. 2012-511329/US20100203056 [Patent Document 4] WO2015095404/Japanese Patent Publication No. 2017-501155/US20150210772 [Patent Document 5] WO2016140714 [Non-patent literature]

[Non-Patent Document 1] Thomas A. Mace, et.al, Gut. 2018, 67(2), 320-332. [Non-Patent Document 2] Kristen B. Long et.al, Mol Cancer Ther; 2017, 16(9), 1898-1908. [Non-Patent Document 3] ASCO-GI 2020 Abs.638 https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.4_suppl.638 "HALO 109-301: A randomized, double-blind, placebo-controlled, phase 3 study of pegvorhyaluronidase alfa (PEGPH20) + nab-paclitaxel/gemcitabine (AG) in patients (pts) with previously untreated hyaluronan (HA)-high metastatic pancreatic ductal adenocarcinoma (mPDA).” [Non-Patent Document 4] NCT02767557, https://clinicaltrials.gov/ct2/show/NCT02767557 First Posted: May 10, 2016 Herlev Hospital/Celgene “Study of Nab-Paclitaxel and Gemcitabine With or Without Tocilizumab in Pancreatic Cancer Patients (PACTO)” [Non-Patent Document 5] JapicCTI-194753 https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-194753&language=ja Date of first publication: 2019/05/13 "A Phase I study of tocilizumab and gemcitabine-nab-paclitaxel combination therapy for metastatic pancreatic cancer unresponsive to gemcitabine and nab-paclitaxel. tocilizumab plus gemcitabine/nab-paclitaxel in patient with gemcitabine/nab-paclitaxel-refractory metastatic pancreatic cancer)” [Non-Patent Document 6] Zev A. Wainberg1 et al., Clin Cancer Res. 2020; 26:4814-4822, Published Online First June 18, [PMID: 32554514] https://pubmed.ncbi.nlm.nih.gov/32554514/ [Non-Patent Document 7] National Cancer Research Center Cancer Countermeasure Information Center: National Cancer Patient Surveillance Statistics (Monitoring of Cancer Incidence in Japan: MCIJ2015) Cancer Information Service, Latest Cancer Statistics p.304 https://ganjoho.jp/data/reg_stat/statistics/brochure/mcij2015_report.pdf. [Non-Patent Document 8] Pancreatic Society: Pancreatic Cancer National Registration Survey Report 2007. Pancreas 23: 105-123, 2008. [Non-Patent Document 9] Lancet. 2011 Aug 13; 378 (9791): 607-620. [Non-Patent Document 10] Pancreatic Cancer Diagnosis and Treatment Guidelines 2019 Edition http://www.suizou.org/pdf/pancreatic_cancer_cpg-2019.pdf [Non-Patent Literature 11] Lancet. 2016 Feb 6; 387 (10018): 545-557. [Non-Patent Document 12] J. Clin. Oncol., 2018 Feb, 1: 36 (4): 359-66. [Non-Patent Document 13] Cancer Cell. 2012 Mar 20; 21 (3): 418-29 [Non-Patent Document 14] Ann Rheum Dis 2000; 59 (suppl 1): i21-i27 [Non-Patent Document 15] J Med Diagn Meth 6 (1): 234, 2017. [Non-Patent Document 16] Schmid P, et al. N Engl J Med 2018; 379: 2108-21. [Non-Patent Document 17] Rittmeyer A, et al. Lancet 2017; 389: 255-65

[Problems to be Solved by Invention]

The present invention provides a novel combination of agents for the treatment of pancreatic cancer. The novel combination of the present invention can be used in addition to, or in place of, existing therapies (including chemo-radiotherapy, primary chemotherapy, and secondary chemotherapy) as described in FIG. 12 . [Technical means to solve problems]

In particular, the present invention provides a novel concomitant therapy using either or both of an IL-6 inhibitor and a PD-1/PD-L1 signaling inhibitor in addition to standard therapy using at least one chemotherapeutic agent. Representative examples of known chemotherapeutic agents that can be combined with IL-6 inhibitors and/or PD-1/PD-L1 signaling inhibitors include single-dose gemcitabine hydrochloride (GEM), or combined use of GEM and nab-paclitaxel .

Through intensive research, the inventors of the present invention found that a combination of agents including chemotherapeutic agents, IL-6 signaling inhibitors and/or PD-1/PD-L1 signaling inhibitors can improve the therapeutic effect of currently difficult-to-treat pancreatic cancer , thereby completing the present invention. For example, the inventors of the present invention found that the combination of anti-interleukin-6 (IL-6) receptor antibodies in patients with unresectable or recurrent pancreatic cancer unresponsive to low-molecular-weight chemotherapeutics can eliminate the need for low-molecular-weight chemotherapeutic agents. Anergy to therapeutic agents and improved immunosuppression for effective treatment of pancreatic cancer. Furthermore, the present inventors found that connective tissue hyperplasia is inhibited by blocking IL-6 signaling with an anti-IL-6R antibody. The inventors of the present invention further found that this action increases the absorption of the low molecular weight drug into the tumor tissue. In addition, it was suggested that the combined use of chemotherapeutic agents and anti-IL-6R antibodies induces not only increased infiltration of low-molecular-weight drugs into tumors, but also increased infiltration of high-molecular-weight antibody preparations or immune cells into tumors. It is also shown that the combination of anti-IL-6R antibody and anti-PD-L1 antibody not only promotes the infiltration and activation of T cells, but also promotes the infiltration and activation of B cells, which may improve the effect of cancer immunotherapy. Furthermore, it has been shown that the combined use of chemotherapeutic agents, anti-IL-6R antibodies and anti-PD-L1 antibodies can exert synergistic anti-tumor effects that cannot be achieved alone or in other combinations.

The inventors of the present invention have successfully demonstrated that in pancreatic cancer tumor tissue, by combining standard therapy gemcitabine with anti-IL-6R antibody (tocilizumab) and anti-PD-L1 antibody (atezolizumab) Specific evidence that the infiltration of CD45-positive immune cells, such as dendritic cells (DC), T cells, and B cells, into tumors is enhanced by administration. The inventors of the present invention, without being bound by theory, believe that in addition to the infiltration of various immune cells, dendritic cells recognize and activate specific cancer antigens, thereby activating T cells and B cells to induce acquired immunity, thereby exerting a significant anti-tumor effect .

That is, the present invention provides the following inventions more specifically. (1) A pharmaceutical composition comprising an immunotherapeutic agent (for example, a CTLA-4 inhibitor, a PD-1 inhibitor, an immune checkpoint inhibitor such as a PD-L1 inhibitor) as an active ingredient, and in combination with IL A -6 inhibitor is used in combination with at least one chemotherapeutic agent to treat pancreatic cancer. (1-1) A pharmaceutical composition containing an IL-6 inhibitor as an active ingredient and used in combination with an immunotherapeutic agent and at least one chemotherapeutic agent to treat pancreatic cancer. (1-2) A pharmaceutical composition comprising a PD-1/PD-L1 signaling inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor) as an active ingredient, and an IL-6 inhibitor, and at least one chemotherapeutic agent for the treatment of pancreatic cancer. (1-3) A pharmaceutical composition containing an IL-6 inhibitor as an active ingredient, and used in combination with a PD-1/PD-L1 signaling inhibitor and at least one chemotherapeutic agent, to treat pancreatic cancer .

(2) The aforementioned pharmaceutical composition, wherein the aforementioned chemotherapeutic agent is a pyrimidine-based, taxane-based, platinum-based, folinic acid, camptothecin derivative, or molecular targeted drug. (2-1) The aforementioned pharmaceutical composition, wherein the aforementioned chemotherapeutic agent is a pyrimidine-based, taxane-based, or platinum-based drug. (2-2) The above pharmaceutical composition, wherein the chemotherapeutic agent is a pyrimidine-based agent selected from fluorouracil, tegafur, gemcitabine and capecitabine, and/or selected from paclitaxel, nab-paclitaxel and paclitaxel A taxane-based drug in the group, and/or a platinum-based drug selected from cisplatin and oxaliplatin. (2-3) The above-mentioned pharmaceutical composition, wherein the above-mentioned chemotherapeutic agent is gemcitabine or a pharmaceutically acceptable salt thereof. (2-4) The pharmaceutical composition as described above, wherein the chemotherapeutic agent is gemcitabine or a pharmaceutically acceptable salt thereof, and nanoparticles comprising albumin and taxane. (2-5) The above-mentioned pharmaceutical composition, wherein the above-mentioned chemotherapeutic agents are gemcitabine hydrochloride and nab-paclitaxel (Abraxane ^{( registered trademark )} ).

(3) The aforementioned pharmaceutical composition, wherein the aforementioned IL-6 inhibitor is an anti-IL-6R antibody. (3-1) The pharmaceutical composition according to (3), wherein the anti-IL-6R antibody is tocilizumab, satrilizumab, or salimumab. (3-2) The pharmaceutical composition according to (3), wherein the anti-IL-6R antibody is tocilizumab. (3-3) The pharmaceutical composition according to (3), wherein the anti-IL-6R antibody is satelizumab.

(4) The aforementioned pharmaceutical composition, wherein the aforementioned PD-1/PD-L1 signaling inhibitor is a PD-1 antagonist or a PD-L1 antagonist. (4-1) The pharmaceutical composition according to (4), wherein the PD-1/PD-L1 signaling inhibitor is a PD-1 antagonist. (4-2) The pharmaceutical composition according to (4), wherein the PD-1/PD-L1 signaling inhibitor is a PD-L1 antagonist. (4-3) The pharmaceutical composition according to (4-1), wherein the PD-1 antagonist is an anti-PD-1 antibody. (4-4) The pharmaceutical composition according to (4-1), wherein the PD-1 antagonist is AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab benzizumab (MK-3475), REGN2810, PDR001, BGB-A317 or pidilizumab (CT-011).

(5) The pharmaceutical composition according to (4-2), wherein the PD-L1 antagonist is an anti-PD-L1 antibody. (5-1) The pharmaceutical composition according to (4-2), wherein the PD-L1 antagonist is durvalumab, atezolizumab, avelumab, BMS-936559, MSB0010718C, MPDL3280A, or MEDI4736. (5-2) The pharmaceutical composition according to (4-2), wherein the PD-L1 antagonist is atezolizumab. (6) The above pharmaceutical composition, wherein the chemotherapeutic agent, the IL-6 signaling inhibitor and the PD-1/PD-L1 signaling inhibitor are administered simultaneously, separately, or continuously.

(7) A medicine containing atezolizumab, which is used by a method comprising combining the medicine containing atezolizumab with tocilizumab, gemcitabine, or a pharmaceutically acceptable salt thereof and nab-paclitaxel in combination with nab-paclitaxel for the treatment of pancreatic cancer in human subjects, and the subjects are administered at the following dosages: (i) tocilizumab at a dose of 8 mg/kg once at 4-week intervals (Q4W); and atezolizumab were selected from the group consisting of 840 mg once with a 2-week interval (Q2W), 1200 mg once with a 3-week interval (Q3W), and 1680 mg once with a 4-week interval (Q4W). group; (ii) the dose of tocilizumab was 4 mg/kg once with 2-week intervals (Q2W); and the dose of atezolizumab was selected from the group consisting of 840 mg once with 2-week intervals (Q2W), Cohort consisting of 1200 mg once with 3-week interval (Q3W) and 1680 mg once with 4-week interval (Q4W); (iii) Tocilizumab at 8 mg/kg once with 2-week interval (Q2W) ); and the dose of atezolizumab was selected from the group consisting of 840 mg once with a 2-week interval (Q2W), 1200 mg once with a 3-week interval (Q3W), and 1680 mg once with a 4-week interval (Q4W). (iv) Tocilizumab at a dose of 8 mg/kg once every 4 weeks (Q4W); and atezolizumab at a dose of 1680 mg once at a 4-week interval (Q4W); Administer nab-paclitaxel and gemcitabine hydrochloride once a week for 3 consecutive weeks, and discontinue the drug in the 4th week. The dose of nab-paclitaxel is 125 mg/m ² (body surface area) based on paclitaxel once, and the dose of gemcitabine hydrochloride is calculated as gemcitabine Count 1000 mg/m ² (body surface area) once. (7-1) A medicine containing tocilizumab, which is used by the following method: The method comprises the steps of combining the medicine containing tocilizumab with atezolizumab, gemcitabine or a pharmaceutically acceptable salt thereof and nab-paclitaxel in combination with nab-paclitaxel for the treatment of pancreatic cancer in human subjects, and the subjects are administered at the following dosages: (i) tocilizumab at a dose of 8 mg/kg once at 4-week intervals (Q4W); and atezolizumab were selected from the group consisting of 840 mg once with a 2-week interval (Q2W), 1200 mg once with a 3-week interval (Q3W), and 1680 mg once with a 4-week interval (Q4W). group; (ii) the dose of tocilizumab was 4 mg/kg once with 4-week intervals (Q4W); and the dose of atezolizumab was selected from the group consisting of 840 mg once with 2-week intervals (Q2W), Cohort consisting of 1200 mg once with 3-week interval (Q3W) and 1680 mg once with 4-week interval (Q4W); (iii) Tocilizumab at 8 mg/kg once with 2-week interval (Q2W) ); and the dose of atezolizumab was selected from the group consisting of 840 mg once with a 2-week interval (Q2W), 1200 mg once with a 3-week interval (Q3W), and 1680 mg once with a 4-week interval (Q4W). (iv) Tocilizumab at a dose of 8 mg/kg once every 4 weeks (Q4W); and atezolizumab at a dose of 1680 mg once at a 4-week interval (Q4W); Administer nab-paclitaxel and gemcitabine hydrochloride once a week for 3 consecutive weeks, and discontinue the drug in the 4th week. The dose of nab-paclitaxel is calculated as paclitaxel at 125 mg/ ^m2 (body surface area) once, and the dose of gemcitabine hydrochloride is calculated as gemcitabine Count 1000 mg/m ² (body surface area) once.

(8) A medicament containing an IL-6 signaling inhibitor for administration in combination with a chemotherapeutic agent in the treatment of cancer to enhance the effect of the chemotherapeutic agent, The chemotherapeutic agent and the IL-6 signaling inhibitor are administered simultaneously, separately, or sequentially. (8-1) The medicine according to (8), wherein the cancer is resistant to a chemotherapeutic agent. (8-2) A medicine according to (8) for treating a cancer resistant to a chemotherapeutic agent, in a group (patients) comprising an individual requiring treatment of a cancer resistant to a chemotherapeutic agent cohort), the rate of remission or disease control in the cohort was increased compared to the case where the chemotherapeutic agent was administered without combination with an IL-6 signaling inhibitor. (8-3) A medicine containing an IL-6 signaling inhibitor for treating cancer resistant to a chemotherapeutic agent and administered in combination with a chemotherapeutic agent or in combination with a chemotherapeutic agent, wherein the chemotherapeutic agent is administered Simultaneous, separate, or sequential administration with the IL-6 signaling inhibitor, In a cohort comprising individuals in need of treatment of chemotherapeutic-resistant cancers, the rate of remission or disease in the cohort is increased compared to the case where the chemotherapeutic agent is administered without a combination of an IL-6 signaling inhibitor control rate. (8-4) A medicine containing an IL-6 signaling inhibitor as described in (8) or (8-1) above, wherein (a) the aforementioned group comprising individuals in need of treatment of chemotherapeutic-resistant cancers comprises individuals who have not been diagnostically investigated for resistance prior to administration of the chemotherapeutic agent; or (b) the above-mentioned cancers that are resistant to chemotherapeutic agents are cancers that are innately resistant to chemotherapeutic agents; or (c) the above-mentioned cancer that is resistant to a chemotherapeutic agent is a cancer that has acquired resistance to a chemotherapeutic agent; or (d) The above-mentioned cancers that are resistant to chemotherapeutic agents are cancers that recur after administration of the chemotherapeutic agents.

(9) A pharmaceutical composition or kit comprising an anti-IL-6R antibody and an anti-PD-L1 antibody, which is used in combination with a chemotherapeutic agent to treat pancreatic cancer. (9-1) The pharmaceutical composition or set according to (9), wherein the pancreatic cancer is pancreatic cancer that is inherently resistant to a chemotherapeutic agent or has acquired resistance to a chemotherapeutic agent, and the pharmaceutical composition Or the kit is characterized by the use of chemotherapeutic agents in combination with the anti-IL-6R antibody and the anti-PD-L1 antibody to increase the efficiency of the administered population. (9-2) A pharmaceutical composition or kit comprising an anti-IL-6R antibody and an anti-PD-L1 antibody for treating pancreatic cancer in an individual who needs to treat pancreatic cancer that has recurred after administration of a chemotherapeutic agent.

(10) An IL-6 inhibitor-containing composition for promoting the penetration of the above-mentioned cancer therapeutic agent into cancer tissue in the treatment of cancer in an individual using the cancer therapeutic agent. (10-1) A method for promoting the penetration of the above-mentioned cancer therapeutic agent into cancer tissue for treating cancer in an individual, characterized in that the above-mentioned method comprises administering a pharmaceutical composition containing an IL-6 inhibitor, the above-mentioned pharmaceutical composition The composition is administered in combination with the above-mentioned therapeutic agents. (10-2) The composition according to (10) or the method according to (10-1), wherein the individual is a human. (10-3) The composition according to (10) or the method according to (10-1), wherein the above-mentioned cancer is a cancer with high fibrosis and/or a dense stroma. (10-4) The composition according to (10) or the method according to (10-1), wherein the cancer is pancreatic cancer or lung cancer. (10-5) The composition according to (10) or the method according to (10-1), wherein the drug for the treatment of cancer is a drug with a molecular weight of 400 or less. (10-6) The composition according to (10) or the method according to (10-1), wherein the drug for treating cancer is a chemotherapeutic agent with a molecular weight of 400 or less. (10-7) The composition according to (10) or the method according to (10-1), wherein the drug for the treatment of cancer is gemcitabine and a pharmaceutically acceptable salt thereof. (10-8) The composition according to (10) or the method according to (10-1), wherein the IL-6 inhibitor is an anti-IL-6R antibody such as tocilizumab.

(11) A composition comprising an IL-6 inhibitor for use in promoting infiltration of CD45 positive cells into a target tissue in an individual. (11-1) A method of promoting the infiltration of CD45-positive cells into a target tissue in an individual, wherein the above method is characterized by administering a pharmaceutical composition comprising an IL-6 inhibitor. (11-2) The composition according to (11) or the method according to (11-1), wherein the individual is a human. (11-3) The composition according to (11) or the method according to (11-1), wherein the target tissue is an IL-6 overexpressing tissue. (11-4) The composition according to (11) or the method according to (11-1), wherein the target tissue is a collagen overproducing tissue. (11-5) The composition according to (11) or the method according to (11-1), wherein the target tissue is a tumor tissue. (11-6) The composition or method according to (11-5), wherein the tumor tissue is highly fibrous and/or tissue containing relatively dense stroma. (11-7) The composition or method according to (11-5) or (11-6), wherein the tumor tissue is pancreatic cancer or lung cancer.

(12) A method of promoting the infiltration of immune cells (eg, CD45-positive immune cells) into target tissues of an individual, wherein the method is characterized in that a pharmaceutical composition comprising an IL-6 inhibitor and PD-1/PD-L1 signaling are combined Inhibitor combination administration. (12-1) A composition comprising an IL-6 inhibitor administered in combination with a PD-1/PD-L1 signaling inhibitor to promote infiltration of T cells, dendritic cells and B cells into target tissues in an individual . (12-2) A composition comprising a PD-1/PD-L1 signaling inhibitor administered in combination with an IL-6 inhibitor to promote infiltration of T cells, dendritic cells and B cells into target tissues in an individual . (12-3) The method according to (12), or the composition according to (12-1) or (12-2), wherein the target tissue is an IL-6 overexpressing tissue. (12-4) The method according to (12), or the composition according to (12-1) or (12-2), wherein the target tissue is a tumor tissue. (12-5) The method or composition according to (12-4), wherein the tumor tissue is pancreatic cancer or lung cancer. (12-6) A medicine composed of a PD-1/PD-L1 signaling inhibitor and an IL-6 inhibitor, which is used in the treatment of cancer to promote immune cells (such as CD45 positive immune cells) to target tissues of infiltration. (12-7) The medicine according to (12-6), wherein the immune cells are T cells, dendritic cells and B cells. (12-8) A medicine composed of a PD-1/PD-L1 signaling inhibitor and an IL-6 inhibitor, which is used for combined treatment based on cancer immunotherapy.

(13) A PD-1/PD-L1 signaling inhibitor for treating pancreatic cancer in combination with at least one chemotherapeutic agent and an IL-6 signaling inhibitor. (13-1) An IL-6 inhibitor for treating pancreatic cancer in combination with at least one chemotherapeutic agent and a PD-1/PD-L1 signaling inhibitor. (13-2) The PD-1/PD-L1 signaling inhibitor according to (13) or the IL-6 inhibitor according to (13-1), wherein the chemotherapeutic agent is selected from fluorouracil, tegafur, A pyrimidine-based agent in gemcitabine and capecitabine, and/or a taxane-based agent selected from the group consisting of paclitaxel, nab-paclitaxel, and paclitaxel, and/or selected from cisplatin and oxaliplatin of platinum-based drugs. (13-3) The PD-1/PD-L1 signaling inhibitor according to (13) or the IL-6 inhibitor according to (13-1), wherein the chemotherapeutic agent is gemcitabine or a pharmaceutically acceptable salt thereof . (13-4) The PD-1/PD-L1 signaling inhibitor according to (13) or the IL-6 inhibitor according to (13-1), wherein the chemotherapeutic agent is gemcitabine or a pharmaceutically acceptable salt thereof , and nanoparticles containing albumin and taxanes. (13-5) The above PD-1/PD-L1 signaling inhibitor or IL-6 inhibitor, wherein the above IL-6 inhibitor is an anti-IL-6R antibody. (13-6) The aforementioned PD-1/PD-L1 signaling inhibitor or IL-6 inhibitor, wherein the aforementioned PD-1/PD-L1 signaling inhibitor is a PD-1 antagonist (eg, an anti-PD-1 antibody) ) or PD-L1 antagonists (eg, anti-PD-L1 antibodies). (13-7) The above PD-1/PD-L1 signaling inhibitor or IL-6 inhibitor, wherein the chemotherapeutic agent, the IL-6 signaling inhibitor and the PD-1/PD-L1 signaling inhibitor are administered simultaneously , separate administration, or continuous administration.

(14) Use of a PD-1/PD-L1 signaling inhibitor for the treatment or prevention of pancreatic cancer in combination with at least one chemotherapeutic agent and an IL-6 signaling inhibitor, or for the manufacture of such treatment or Preventive Medicine. (14-1) Use of an IL-6 signaling inhibitor for the treatment of pancreatic cancer in combination with at least one chemotherapeutic agent and a PD-1/PD-L1 signaling inhibitor, or manufacture for such treatment or Preventive Medicine. (14-2) The use according to (14) or (14-1), wherein the chemotherapeutic agent is a pyrimidine-based agent selected from fluorouracil, tegafur, gemcitabine and capecitabine, and/or selected from paclitaxel , a taxane-based drug in the group consisting of albumin-bound paclitaxel and European paclitaxel, and/or a platinum-based drug selected from cisplatin and oxaliplatin. (14-3) The use according to (14) or (14-1), wherein the chemotherapeutic agent is gemcitabine or a pharmaceutically acceptable salt thereof. (14-4) The use according to (14) or (14-1), wherein the chemotherapeutic agent is gemcitabine or a pharmaceutically acceptable salt thereof, and nanoparticles comprising albumin and taxane. (14-5) The above-mentioned use, wherein the above-mentioned IL-6 inhibitor is an anti-IL-6R antibody. (14-6) The use as above, wherein the PD-1/PD-L1 signaling inhibitor is a PD-1 antagonist (eg, anti-PD-1 antibody) or a PD-L1 antagonist (eg, anti-PD-L1 antibody). (14-7) The use as described above, wherein the chemotherapeutic agent, the IL-6 signaling inhibitor and the PD-1/PD-L1 signaling inhibitor are administered simultaneously, separately, or continuously.

(15) A method of treating a human subject diagnosed with pancreatic cancer, comprising administering to the subject a medicament comprising tocilizumab, gemcitabine, nab-paclitaxel, and atezolizumab at the following doses: ( i) The dose of tocilizumab is 8 mg/kg once with a 4-week interval (Q4W); and the dose of atezolizumab is selected from 840 mg once with a 2-week interval (Q2W), 1200 mg once mg at 3-week intervals (Q3W) and 1680 mg once at 4-week intervals (Q4W); (ii) tocilizumab at 4 mg/kg once at 2-week intervals (Q2W); and The dose of atezolizumab was selected from the group consisting of 840 mg once with a 2-week interval (Q2W), 1200 mg once with a 3-week interval (Q3W), and 1680 mg once with a 4-week interval (Q4W) (iii) the dose of tocilizumab is 8 mg/kg once with 2-week intervals (Q2W); and the dose of atezolizumab is selected from the group consisting of 840 mg once with 2-week intervals (Q2W), 1 A group consisting of 1200 mg once with a 3-week interval (Q3W) and 1680 mg once with a 4-week interval (Q4W). (15-2) A method of treating a human subject diagnosed with pancreatic cancer, comprising administering to the subject tocilizumab, gemcitabine, nab-paclitaxel and atezolizumab in the following doses: (iv ) tocilizumab at 8 mg/kg once with 4-week intervals (Q4W); atezolizumab at 1680 mg once with 4-week intervals (Q4W); and weekly for 3 consecutive weeks Administer nab-paclitaxel and gemcitabine hydrochloride once, and stop the drug in the 4th week. The dose of nab-paclitaxel is 125 mg/m ² (body surface area) calculated on paclitaxel once, and the dose of gemcitabine hydrochloride is 1000 mg/m calculated by gemcitabine once. ² (body surface area). [Effect of invention]

The effectiveness of the existing standard therapy can be improved by the medicine, treatment method, kit and use of the present invention. Furthermore, it is possible to overcome the drug resistance of cases in which the existing standard treatment is ineffective, and to restore the effect of chemotherapy again. Furthermore, the choice of therapy can be expanded by combining it with other treatment options that have hitherto been unapproved due to their ineffectiveness. In addition, it is possible to treat pancreatic cancer patients for whom standard therapy or transplantation therapy cannot be performed due to reasons such as advanced age or organ function, and there is no effective treatment option available.

Description of General Expressions and Phrases Used in the Specification The present invention relates to a medicament for the treatment of pancreatic cancer in an individual. Furthermore, the present invention relates to a method for treating pancreatic cancer in an individual. Furthermore, the present invention relates to the use of a medicament for the manufacture of a medicament or a kit for treating pancreatic cancer in an individual.

"Treatment," "treat," or "treating," also known as "treating," "treating," means reducing, alleviating, or alleviating a disease or symptom, and also includes preventing (preventing) future disease or symptom onset or inhibit disease progression. Expected therapeutic effects from treatment include: relief of symptoms, alleviation of any direct or indirect pathological consequences of disease, slowing of progression of symptomatic exacerbations, restoration or alleviation of disease state, and improved prognosis. "Treatment" or "treatment" is not limited to "treatment" or "treatment" that results in a certain cure or cure of the disease or symptom, nor is it limited to "treatment" or "treatment" that is effective if the desired therapeutic effect is obtained. For example, the so-called cancer treatment (or cancer treatment) means that for a subject suffering from cancer or diagnosed with cancer, in order to reduce the number of cancer cells, reduce the size of the tumor, slow the infiltration rate of cancer cells to peripheral organs, or slow down the tumor At least one desired therapeutic effect, such as metastasis or tumor growth rate, is administered, and surgery, radiation therapy, and the like are performed. In one embodiment of the present invention, the so-called cancer treatment refers to treatment using the medicine, set, and treatment method of the present invention.

In one aspect of the present invention, the pancreatic cancer is recurrent or treatment-resistant pancreatic cancer. In addition, in the present invention, pancreatic cancer may be a pancreatic cancer with congenital drug resistance, acquired drug resistance, or recurrence. In addition, in the present invention, pancreatic cancer may be pancreatic cancer that has no standard treatment and is intolerant, unresponsive or recurring to one or more existing chemotherapy regimens. Also, the pancreatic cancer may be recurrent/treatment-resistant pancreatic cancer. Pancreatic cancer may be pancreatic cancer that has no standard treatment and is intolerant, unresponsive, or recurring to more than one existing chemotherapy regimen.

The terms "drug resistance," "anergy," and "resistance" are used synonymously, so long as a cell or individual is unresponsive (also known as susceptibility) to treatment or treatment of the disease, and/or produces a significant The state of reduced ability to respond (eg, partial remission and/or complete remission) is not limited. For example, a so-called chemotherapeutic-resistant pancreatic cancer is a pancreatic cancer that is completely unresponsive to treatment with chemotherapy, or has no significant response such as partial remission or complete remission. Even if the drug is administered to pancreatic cancer that is "drug-resistant" or "unresponsive" to the drug, the desired effect will not be obtained. Moreover, it may even progress further and turn into a highly malignant pancreatic cancer. "Drug resistance" or "anergy" can be either "innate drug resistance" or "acquired drug resistance".

The term "intrinsic resistance" refers to the innate unresponsiveness of a cell or individual to an agent. If a cell or individual is innately resistant to an agent, it results in a state in which the agent is ineffective or less effective than would be the case without resistance (ie, sensitivity or responsiveness). The effective rate of any drug treatment cannot reach 100%, and there must be people who are ineffective and unresponsive to the drug. The effectiveness of pharmaceuticals for asthma, cancer, depression, diabetes, peptic ulcer, hyperlipidemia, etc. is generally about tens of percent.

The term "acquired resistance" refers to a cell or individual that is originally responsive (or sensitive) to an agent, but acquires anergy due to exposure to the agent. Acquired resistance can lead to a state in which an initially effective agent becomes ineffective during administration, or is less effective than a situation without resistance (ie, a responsive situation). In particular, the acquired drug resistance of the medicine of the present invention may be drug resistance developed after previous treatment. For example, anti-angiogenic therapeutic agents are generally used for the treatment of various cancers including liver cancer, but they are effective in the initial stage of treatment, and may acquire resistance soon after repeated treatment is continued. For example, pancreatic cancer that is resistant to chemotherapeutic agents has not regressed or even progressed further in the presence of chemotherapeutic agents.

The term "recurrence" refers to the re-confirmation of the appearance or growth of cancer after the cancer has been temporarily cured or shrunk by treatment. Although the treatment seems to be successful, the re-emergence of tiny cancerous foci that cannot be seen with the naked eye that was not completely removed by surgery, or the cancer that was temporarily shrunk by drug therapy (anticancer drug treatment) or radiation therapy re-expands, causing " relapse". "Recurrence" sometimes refers to the occurrence of the same type of cancer in the same location as the treated cancerous part or near it, and sometimes the same type of cancer occurs in a different organ or organ from the treated cancerous part. The occurrence of the same type of cancer in a different organ or organ from the treated cancer is specifically referred to as "metastasis". Cancer cells enter blood vessels or lymphatics from the site where they were originally generated, and then move to other organs or organs with the flow of blood or lymphatics, where they grow. Most cancers metastasize to lymph nodes, lungs, liver, brain, bone and other places with rich blood flow. When cancer occurs due to recurrence, the individual with the cancer has received prior treatment such as drug therapy or radiation therapy. Thus, cancers that recur may be cancers that are acquired resistance to previous treatments.

The method for judging whether pancreatic cancer is resistant to a chemotherapeutic agent is not limited as long as it is a method capable of judging. For example, it is possible to detect the specificity of the cancer having such resistance in the cancer tissue collected before the treatment. The presence or absence of markers of sexual expression, such as genes, proteins, and histological characteristics, is used as a criterion for discrimination. The practitioner can arbitrarily select a genetic or histological method for discrimination among known methods. Specific markers can be, for example, cell-free DNA in blood or the expression of CA19-9 (carbohydrate antigen 19-9), p16 or BRCA2 gene mutation in cancer tissue, or cancer The number or ratio of cells in a tissue expressing the gene or protein. In addition, when the therapeutic effect expected by the treatment of the cancer described later is not obtained, or the effect is lost or reduced after the previous treatment with chemotherapy, the cancer can also be judged to be resistant to the chemotherapeutic agent.

The therapeutic effect, that is, the effectiveness, produced by the treatment of cancer can be evaluated according to the methods or indicators exemplified in this specification, or one or a plurality of known methods or indicators (refer to W.A.Weber, J.Nucl.Med.50: 1S -10S (2009)). For example, regarding tumor growth inhibition, according to the National Cancer Institute (NCI) benchmark, T/C below 42% is the lowest level of anti-tumor activity. T/C<10% was regarded as a high level of anti-tumor activity, T/C (%)=median value of tumor volume of treated subjects/median value of tumor volume of control group×100.

In one embodiment, the therapeutic effect produced by the treatment of cancer, that is, the effectiveness of the anti-cancer effect can be evaluated based on one or more known indicators regarding the state of the patient, diseased organ, or diseased cell. As such an index, for example, a "response rate", which indicates the ratio of patients whose cancer cells are shrunk or eliminated after a certain cancer treatment method is administered to a patient, is given. In addition, the "disease control rate (DCR)" is a ratio obtained by adding the remission rate which is the sum of CR (complete remission) and PR (partial remission) to SD (stable) which is a state in which the size of the tumor does not change. . Further, there may be mentioned: partial remission (PR), complete remission (CR), overall remission rate (ORR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), pathologically complete remission (pCR), and clinical complete remission (cCR).

ORR refers to the proportion of patients who show a reduction in the size or number of cancers and maintain a minimum time limit, and ORR can be expressed as the sum of the complete remission rate and the partial remission rate. DCR refers to the proportion of patients whose disease has not deteriorated, and can be expressed as the sum of the complete remission rate, the partial remission rate, and the stable disease rate (SD). PFS, also known as "time to tumor progression," represents the length of time during and after treatment that a cancer progression-free patient survives, including the time a patient experiences CR or PR, and the time to SD. DFS refers to the length of time during and after treatment that a patient survives without recurrence or other disease. OS refers to the time a subject has survived since the start of treatment. Prolongation of OS by treatment refers, for example, to the extension of the point-predicted value of median survival from the start of the trial in the cohort of patients receiving treatment compared to the cohort of patients without treatment. The above-mentioned "group" refers to a collection comprising individuals in need of cancer treatment, that is, a "patient group".

The assessment of anergy and/or responsiveness can be performed using well-known methods in the art and is not limited as long as the desired assessment can be performed. For example, anergy and/or responsiveness can be assessed by in vivo or in vitro analysis of disease-derived cell growth, etc., under treatment (eg, treatment with an agent). The acquisition of anergy, the maintenance of responsiveness, and/or the increase in anergy can also be assessed by in vivo or in vitro analysis of the growth of disease-derived cells, and the like. In one embodiment, anergy may be indicated by a change in _IC50 , _EC50 , or growth or decrease in cells derived from disease. In one embodiment, the variation can be greater than any of about 50%, 100%, and/or 200%. Also, changes in anergy and/or responsiveness can be assessed in vivo, eg, by assessing response to treatment, duration of response, and/or periods of no exacerbation, eg, partial and complete remission. Changes in anergy and/or responsiveness can also be based on changes in response to treatment, duration of response, and/or exacerbation-free periods, such as the number of partial responses and/or complete responses, in a group of individuals.

In one embodiment, the response to treatment by the medicine, set, and treatment method of the present invention is PR, CR, PFS, DFS, ORR, DCR assessed using the Response Criteria for Solid Cancer (RECIST) 1.1 Response Criteria or any of the OS.

In one embodiment, specific efficacy-determining markers can be used to assess the efficacy of treatment of cancer. Serum CA19-9 levels in subjects following administration of a composition comprising nanoparticles comprising a PD-1/PD-L1 signaling inhibitor and albumin are reduced by at least about 50% compared to pre-treatment serum CA19-9 levels ( at least about any of 60%, 70%, 80%, 90%, 95%, etc.).

All embodiments of the present invention are not effective for all subjects to achieve the desired therapeutic effect, and should be understood to be effective for achieving the desired therapeutic effect by Student's T test, chi-square test, Mann-Whitney U test, KW (Kruskal-Wallis) test (H test) ), JT (Jonckheere-Terpstra) test and Wilcoxon test, etc. any statistical test known in the art to determine the statistically significant number of objects, any one of the embodiments of the present invention achieves the desired therapeutic effect.

As long as the efficacy is confirmed based on at least one of the indicators exemplified in the present specification or known indicators for evaluating the therapeutic effect of cancer, the treatment can be judged to be effective or to have an anticancer effect. The effectiveness is preferably related to the prolongation of the patient's survival period, or the improvement of systemic symptoms such as pain relief, and the treatment can also be judged when the treatment effect such as the reduction or temporary disappearance of cancer, or the reduction of serum CA19-9 is obtained. efficient. Furthermore, "more effective", "higher effectiveness", "higher therapeutic effect" or "improved therapeutic effect" compared to the comparison object means to compare with at least one of the indexes exemplified here or known indexes More effective.

"About" used when modifying a numerically defined parameter (such as the dose of an agent, or the length of treatment with a concomitant therapy described in this specification) means that the parameter is sometimes 10% above or below the value stated for the parameter change within the range. For example "about 5 mg" means "4.5 mg to 5.5 mg".

The composition or medicament of the present invention can be administered in the form of pharmaceuticals, orally or parenterally, systemically or locally. For example, intravenous injection such as drip, intramuscular injection, intraperitoneal injection, subcutaneous injection, suppository, enteral injection, oral enteric solvent, etc. can be selected, and an appropriate administration method can be selected according to the age and symptoms of the patient. The subject to which the composition or medicament of the present invention is administered is a mammal. The mammal is preferably a human.

According to the usual method, the preparation can be prepared into lozenges, granules, powders, capsules, emulsions, suspensions, syrups, or injections such as sterile solutions and suspensions. When these active ingredients are separately formulated to prepare two or more kinds of preparations, the respective preparations may be administered simultaneously, or may be administered separately or continuously at a predetermined time interval. The two or more preparations may be administered at different times in one day. The medicament of the present invention can be administered systemically or locally orally or parenterally. When these active ingredients are separately formulated to prepare two or more formulations, each formulation may be administered by different routes.

In one embodiment, the so-called "simultaneous administration, separate administration or continuous administration" refers to the amount and administration of the compound of the present invention or a pharmaceutically acceptable salt thereof, and other active ingredients in order to achieve the desired combined therapeutic effect. The relative time point of giving is selected and administered. The compounds of the present invention can be administered by various routes, such as parenteral, subcutaneous, intravenous, intraarticular, subarachnoid, intramuscular, intraperitoneal, topical, and intradermal injection, as well as transdermal, rectal, buccal Topical, oral mucosa, nasal, ocular, as well as inhalation and implantable administration. In one embodiment, whichever is administered first may be administered. In the case of simultaneous administration, the active ingredients may be administered in the same or different pharmaceutical compositions. Adjuvant therapy, that is, using one active ingredient as a treatment, and using other active ingredients to support the one treatment is also an embodiment of the present invention.

The present invention relates to a combination of two or more medicaments for improved medical use. Each agent can be administered at one time, divided into multiple administrations, or administered by continuous infusion. Two or more drugs may be administered simultaneously, separately, or consecutively. In addition, two or more kinds of drugs can be administered at a specific dose and at a specific interval. In the case where the medicine of the present invention is prepared into a plurality of different preparations and is highly likely to be administered at the same time or at specific intervals, it can be included in documents such as the accompanying instructions or sales brochures of the commercially available medicines. Record and use the main points of each. Alternatively, kits or Kit-of-Parts containing formulations containing each can be made. The kit may contain means such as containers, separate vials or separate packets, pouches, etc., for respectively holding two or more different pharmaceutical compositions (at least one of which contains the agent of the present invention as an active ingredient). The kits are particularly suitable for administering different dosage forms such as oral and parenteral dosage forms, administering each composition at different administration intervals, or setting the doses of each composition relatively. In order to improve adaptability, a set of dosing instructions are usually provided together.

The preparations are prepared by mixing the desired active ingredients with any selected pharmacologically acceptable carriers, excipients or stabilizers to prepare freeze-dried preparations or aqueous solutions for future use. Examples of materials acceptable for formulation include sterile water or physiological saline, stabilizers, excipients, buffers, preservatives, surfactants, chelating agents (EDTA, etc.), binding agents, and the like.

Examples of the surfactant include nonionic surfactants, and typical examples include sorbitan fatty acids such as sorbitan monocaprylate, sorbitan monolaurate, and sorbitan monopalmitate. Esters; glycerol fatty acid esters such as glycerol monocaprylate, glycerol monomyristate, and glycerol monostearate, etc. having HLB 6 to 18, and the like.

In addition, as the surfactant, an anionic surfactant can be mentioned, and typical examples include alkanes having an alkyl group having 10 to 18 carbon atoms, such as sodium acetyl sulfate, sodium lauryl sulfate, and sodium oleyl sulfate. Alkyl sulfates; polyoxyethylene alkyl ether sulfates, such as polyoxyethylene sodium lauryl sulfate, with an average added molar number of 2 to 4 ethylene oxide and an alkyl group of 10 to 18 carbon atoms; lauryl Sodium sulfosuccinate and other alkyl sulfosuccinates whose alkyl group has 8 to 18 carbon atoms; natural surfactants, such as lecithin, glycerophospholipid; sphingomyelin such as sphingomyelin; carbon atoms Sucrose fatty acid esters of fatty acids numbered 12 to 18, etc.

Examples of the buffer include: phosphoric acid, citric acid buffer, acetic acid, malic acid, tartaric acid, succinic acid, lactic acid, potassium phosphate, gluconic acid, caprylic acid, deoxycholic acid, salicylic acid, triethanolamine, fumaric acid Acid and other organic acids, etc., or carbonic acid buffer, Tris (tris (tris(hydroxymethyl)aminomethane) buffer, histidine buffer, imidazole buffer, etc.).

In addition, solution preparations can also be prepared by dissolving in aqueous buffers known in the field of solution preparations. The concentration of the buffer is generally 1-500 mM, preferably 5-100 mM, more preferably 10-20 mM.

Examples of saccharides or carbohydrates such as polysaccharides and monosaccharides include glucan, glucose, fructose, lactose, xylose, mannose, maltose, sucrose, trehalose, and raffinose. Examples of sugar alcohols include mannitol, sorbitol, inositol, and the like.

When the preparation is made into an aqueous solution, for example, an isotonic solution containing physiological saline, glucose or other auxiliary agents, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, can be used. Appropriate dissolving aids, such as alcohols (ethanol, etc.), polyols (propylene glycol, PEG, etc.), nonionic surfactants (polysorbate 80, HCO-50), etc., are used together. If necessary, a diluent, a dissolution aid, a pH adjuster, an analgesic, a sulfur-containing reducing agent, an antioxidant, etc. may be further contained.

Description of Abbreviations The following abbreviations may be used in this specification. GEM or Gem or G: gemcitabine hydrochloride; Nab-pac or nab-PTX or N-PTX: paclitaxel (albumin suspension) or albumin-bound paclitaxel; GN: combination therapy of gemcitabine hydrochloride and albumin-bound paclitaxel; ATZ or Atezo Or A: atezolizumab (gene recombination); TCZ or T: tocilizumab; IL-6: interleukin 6; IL-6R: interleukin 6 receptor; PD-1: programmed death Receptor-1 (Programmed death-1), programmed cell death protein 1 (programmed cell death protein 1), CD279, PD1, SLEB2, PDCD1; PD-L1: PD-1 Ligand 1 , programmed death ligand 1 (programmed death ligand 1), CD274, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1, B7 homolog 1 (B7 homolog 1), PDCD1 ligand 1 (PDCD1 ligand 1) ; CTLA4: Cytotoxic T-Lymphocyte Associated Protein 4, CD152; Chemo: chemotherapeutic agent; 5FU: fluorouracil; IV (intravenous administration); IM (intramuscular administration); SC (intradermal administration); CIT: Cancer immunotherapy or Cancer immunotherapy; CRP: C-reactive protein in blood; HR: Hazard ratio; DLT: Dose-limiting toxicity; RECIST: Response criteria for solid cancer; CR (complete response) ; ORR (overall response rate); PFS (progression-free survival); DFS (disease-free survival), OS (overall survival); pCR (pathological complete response); cCR (clinical complete response); RR (remission) PR (partial response or partial response); DCR (disease control rate or Disease control rate); SD (stable disease or stable disease); PD (progressive disease or progressive disease); CRF (case report or Case Report Form); α-SMA: α-smooth muscle actin; IHC: immunohistochemical staining or Immunohistochemistry; HE staining: hematoxylin-eosin staining; MALDI: matrix-assisted laser desorption Ionization or matrix assisted laser desorption/ioniz ation; MALDI-MSI: Mass Spectrometry Imaging or MSI based on MALDI method; MRI: Magnetic Resonance Imaging or MRI; αCHCA: α-cyano-4-hydroxycinnamic acid; PK-PD: Pharmacokinetics (PK)-Pharmacodynamics (PD); TIL: Tumor Infiltrating Lymphocyte; DC: Dendritic cell or Dendritic cell; iRECIST: Modified RECIST v1.1 for immunotherapy. (A guideline for data management and data collection for trials testing immunotherapeutics.: Seymour L, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics . Lancet Oncol 2017; 18: e143-52)

Detailing chemotherapeutic agent + IL-6 inhibitor and / or immunotherapeutic agent in one form, the present invention provides a basis for existing standard therapy utilizing at least one chemotherapeutic agent for the treatment of cancer (eg, pancreatic cancer). above, novel concomitant therapy using immunotherapeutics and/or IL-6 inhibitors. The so-called "immunotherapeutic agent" is a drug used for therapy mainly by activating the body's inherent immunity (immune cells) to achieve the purpose of treatment. Immunotherapy for the purpose of treating cancer is particularly referred to as "cancer immunotherapy", and is roughly divided into treatment that activates immune cells that attack cancer cells to increase the immune response; and treatment that inhibits the action of immune response inhibitory molecules. treat. Representative examples of the former treatment method include dendritic cell vaccine therapy, and as the latter treatment method, immune checkpoint inhibitors can be cited. In one form, examples of the immune checkpoint inhibitor include PD-1 inhibitors (PD-1 antagonists), CTLA-4 inhibitors, PD-L1 inhibitors (PD-L1 antagonists), and the like. For example, as the anti-PD-1 antibody, nivolumab (Opdivo ^{( registered trademark )} ) and pembrolizumab (Keytruda ^{( registered trademark )} ), or as the anti-PD-L1 antibody, there may be mentioned: duval Lutuzumab (Imfinzi ^{( registered trademark )} ), atezolizumab (Tecentriq ^{( registered trademark )} ), and avelumab (Bavencio ^{( registered trademark )} ), as anti-CTLA-4 antibodies, include: Monoclonal antibody (Yervoy ^{( registered trademark )} ).

Representative examples of known chemotherapeutic agents that can be combined with IL-6 inhibitors and/or immunotherapeutics are single doses of gemcitabine hydrochloride (GEM), or GEM and albumin-bound paclitaxel when the subject cancer is pancreatic cancer used together, but not limited to this. The type of chemotherapeutic agent can be appropriately selected by the practitioner according to the type of cancer to be treated, the therapeutic effect, the patient's condition, tolerance, and the responsiveness of concomitant therapy.

As "chemotherapeutic agents", various agents have been approved for clinical use mainly as anticancer agents, and many more compounds are under development. Representative chemotherapeutic agents are classified into pyrimidines (fluorouracil, tegafur, gemcitabine, capecitabine, others), taxanes (paclitaxel, nab-paclitaxel, paclitaxel, etc.) according to their chemical structures and actions. , others), platinum series (cisplatin, oxaliplatin, others), folinic acid, camptothecin derivatives, molecular targeted drugs, etc. In the present invention, one or two or more of these chemotherapeutic agents may be used in combination with an IL-6 inhibitor and/or an immunotherapeutic agent. In one form, the chemotherapeutic agent used in the present invention is gemcitabine or a pharmaceutically acceptable salt thereof (eg, gemcitabine hydrochloride). In another form, the chemotherapeutic agents used in the present invention are gemcitabine or a pharmaceutically acceptable salt thereof (such as gemcitabine hydrochloride) and nanoparticles comprising albumin and taxane (such as albumin-bound paclitaxel (Abraxane ^{( registered)) trademark )} )).

Furthermore, the concomitant use of chemotherapeutic agents and IL-6 inhibitors and/or immunotherapeutic agents as standard therapy for pancreatic cancer, which may be adopted in the future, is also included in the scope of the present invention. Detailed information on the preferred usage and dosage of this chemotherapeutic agent can be obtained from sources that can be easily accessed by experts, such as the US FDA, the Japan Pharmaceutical and Medical Device Information Homepage, or the public information of relevant societies.

The so-called "IL-6 inhibitor" or "IL-6 signaling inhibitor" is a substance that blocks the signal transmission mediated by IL-6 and inhibits the biological activity of IL-6. Specific examples of IL-6 inhibitors include substances that bind to IL-6, substances that bind to IL-6 receptors, and substances that bind to gp130. In addition, as IL-6 inhibitors, there can be mentioned: inhibitors of the JAK-STAT pathway or MAP kinase pathway downstream of IL-6 signaling, especially substances that inhibit the phosphorylation of STAT3, which is an important intracellular signal mediated by IL-6 , such as AG490, Ruxolitinib, etc. IL-6 inhibitor is not particularly limited, including: anti-IL-6 antibody, anti-IL-6R antibody, anti-gp130 antibody, IL-6 modified form, soluble IL-6 receptor modified form, IL-6 partial peptide , IL-6 receptor partial peptides, low molecular compounds showing the same activity as these, etc.

Preferable examples of IL-6 inhibitors include IL-6 receptor inhibitors, especially anti-IL-6R antibodies. Examples of anti-IL-6R antibodies (also called anti-IL-6R antibodies) approved for clinical use include tocilizumab, satrilizumab or salimumab, all of which can be used in the present invention. Combination therapy medicine, treatment method, set, use.

In one form, the anti-IL-6R antibody may be an antibody having the same antigen-binding properties as tocilizumab in consideration of the desired function, for example, it may contain a heavy chain and a light chain including tocilizumab. An antibody or an antigen-binding fragment thereof of the amino acid sequence of each CDR in which the amino acid sequence of each hypervariable region (CDR) is the same.

In one embodiment, the medicine can be an antibody comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, 99% sequence identity with the amino acid sequence of tocilizumab or antigen-binding fragments thereof. In one embodiment, the medicament may contain at least 80%, 85%, 90%, 95%, 98%, 99% of the amino acid sequence comprising each CDR in the heavy and light chains of tocilizumab. The antibody or antigen-binding fragment thereof to each CDR of the amino acid sequence of % sequence identity. In one embodiment, the medicament may contain at least 80%, 85%, 90%, 95%, 98%, 99% sequence identity with the amino acid sequence of each of the VH and VL regions of tocilizumab Antibodies or antigen-binding fragments thereof in the VH and VL regions of the amino acid sequences of sex.

In another aspect, the present invention provides an IL-6 inhibitor and an immune checkpoint inhibitor in addition to existing standard therapy using at least one chemotherapeutic agent for the treatment of cancer (eg, pancreatic cancer). Novel combination therapy of either or both (eg PD-1/PD-L1 signaling inhibitors). "PD-1/PD-L1 signaling inhibitors" block the so-called immune checkpoint inhibition mechanism by preventing the binding of PD-1 and PD-L1, thereby reactivating T cells, thereby exerting anti-tumor effects. PD-1/PD-L1 signaling inhibitors include PD-1 antagonists or PD-L1 antagonists. As PD-1/PD-L1 signaling inhibitors currently approved for clinical use, a plurality of anti-PD-1 antibodies or anti-PD-L1 antibodies are known. The PD-1 antagonist is not particularly limited, and includes: AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317 and pidilizumab (CT-011). The PD-L1 antagonist is not particularly limited, and includes durvalumab, atezolizumab, avelumab, BMS-936559, MSB0010718C, MPDL3280A, or MEDI4736.

In one form, the medicine of the present invention is a medicine containing an anti-PD-L1 antibody, more specifically atezolizumab, for treating pancreatic cancer in an individual. The medicine of the present invention may also be expressed as a medicine for treating pancreatic cancer. The first drug containing atezolizumab is used in combination with the second drug containing other drugs for pancreatic cancer of the individual. The other agents can be at least one chemotherapeutic agent, and/or tocilizumab. Therefore, the medicine of the present invention can also be expressed as the first medicine containing atezolizumab used in combination with other second and third medicines for treating pancreatic cancer in an individual. The medicine of the present invention can also be represented as the first medicine containing atezolizumab used in combination with other second, third and fourth medicines for treating pancreatic cancer in an individual. The medicine of the present invention can also be represented as the first medicine containing atezolizumab used in combination with other second, third, fourth and fifth medicines for treating pancreatic cancer in an individual.

In one form, the medicament of the present invention is a medicament containing an anti-interleukin-6 receptor antibody, more specifically tocilizumab, for treating pancreatic cancer in an individual. The medicine of the present invention can also be represented as a first medicine containing tocilizumab used in combination with a second medicine containing other medicines for treating pancreatic cancer in an individual. The other agents can be at least one chemotherapeutic agent, and/or atezolizumab. Therefore, the medicine of the present invention can also be represented as the first medicine containing tocilizumab used in combination with other second and third medicines for treating pancreatic cancer in an individual. The medicine of the present invention can also be represented as the first medicine containing tocilizumab used in combination with other second, third and fourth medicines for treating pancreatic cancer in an individual. The medicine of the present invention can also be represented as the first medicine containing tocilizumab used in combination with other second, third, fourth and fifth medicines for treating pancreatic cancer in an individual.

In the medicine, kit, treatment method and use of the present invention, the chemotherapeutic agents that can be administered in combination with tocilizumab and/or atezolizumab are, for example, known or novel anticancer substances, more specifically For example, pyrimidine-based compounds, taxane-based compounds, platinum preparations, etc., including gemcitabine hydrochloride, oxaliplatin, fluorouracil, tegafur-uracil complex, tegafur-gimos Te-oteracil potassium complex, cisplatin, capecitabine, irinotecan hydrochloride, leucovorin, levofolinate, nab-paclitaxel, erlotinib, paclitaxel, MM-398 One or more chemotherapeutic agents in the group consisting of lipotecan liposome preparations.

For example, when tocilizumab and/or atezolizumab are used in combination, the combination of chemotherapeutic agents can be exemplified: ・Gemcitabine alone, ・Gemcitabine and oxaliplatin, ・Gemcitabine and tegafur-gemoster-oteracil potassium combination (also known as S-1 or TS-1), ・Cisplatin alone, ・Gemcitabine and cisplatin, ・FOLFORINOX (fluorouracil, folinic acid (LV) or levofolinate (l-LV), irinotecan hydrochloride and oxaliplatin), ・Gemcitabine and capecitabine, ・Capecitabine alone, ・Fluorouracil alone, ・Fluorouracil and folinic acid, ・Single tegafur-gimoster-oteracil potassium complex (S-1 or TS-1), ・Gemcitabine and nab-paclitaxel, ・Gemcitabine and erlotinib, ・GTX (Gemcitabine, Paclitaxel and Capecitabine), ・OFF (oxaliplatin, fluorouracil, and leucovorin (LV) or levofolinate (l-LV)), ・CapeOX (capecitabine and oxaliplatin), ・FOLFOX (folinic acid (LV) or levofolinate (l-LV), and fluorouracil and oxaliplatin), ・FOLFIRI (folinic acid (LV) or levofolinate (l-LV), and fluorouracil and irinotecan hydrochloride) ・MM-398 (liposomal formulation of irinotecan), fluorouracil and leucovorin (LV) or levofolinate (l-LV), But not limited to these. In addition, these chemotherapeutic agents are sometimes described in pharmaceutically acceptable salts or solvates as active ingredients of the preparation due to solubility and other reasons, but the dosage of these drugs is usually based on the dosage of the active substance. Regulation.

In one form, anti- IL-6R antibody and anti- PD-L1 antibody , the medicine of the present invention contains anti-interleukin-6 receptor antibody (anti-IL-6R antibody) for treating pancreatic cancer, more specifically The medicine of zizumab, in a group comprising individuals in need of pancreatic cancer treatment, administration of an anti-IL-6R antibody resulted in greater efficacy in the group compared to the situation where no anti-IL-6R antibody was administered improve.

In one form, the medicament of the present invention is a medicament containing an anti-PD-L1 antibody, more specifically atezolizumab, for the treatment of unresectable locally advanced or distant metastatic pancreatic cancer, compared to In the case where no anti-PD-L1 antibody was administered, in a cohort comprising individuals in need of treatment for pancreatic cancer, administration of an anti-PD-L1 antibody resulted in increased efficacy in the cohort. It can be a group of individuals without a treatment history of systemic therapy for metastatic pancreatic cancer, or it can be a group of individuals with a history of prior treatment with systemic therapy for one treatment of metastatic pancreatic cancer.

In one form, the medicament of the present invention is a medicament containing an anti-IL-6R antibody, more specifically tocilizumab, for the treatment of unresectable locally advanced or distant metastatic pancreatic cancer, compared to unresectable medicaments. In the case of administration of an anti-IL-6R antibody, in a group comprising individuals in need of pancreatic cancer treatment, administration of an anti-IL-6R antibody resulted in an increase in the efficiency in the group. It can be a group of individuals without a treatment history of systemic therapy for metastatic pancreatic cancer, or it can be a group of individuals with a history of prior treatment with systemic therapy for one treatment of metastatic pancreatic cancer.

In one form, the medicament of the present invention is a medicament containing an anti-PD-L1 antibody, more specifically atezolizumab, for the treatment of recurrent or treatment-resistant pancreatic cancer, compared to no anti-PD administration - In the case of L1 antibody, in a group comprising individuals in need of pancreatic cancer treatment, administration of an anti-PD-L1 antibody resulted in increased efficacy in the group.

In one form, the medicament of the present invention is a medicament containing an anti-IL-6R antibody, more specifically tocilizumab, for the treatment of recurrent or treatment-resistant pancreatic cancer, compared to no administration of anti-IL-6R In the case of antibodies, in a group comprising individuals in need of pancreatic cancer treatment, administration of an anti-IL-6R antibody resulted in increased efficacy in the group.

In one form, the medicament of the present invention is a medicament containing atezolizumab for the treatment of pancreatic cancer without standard treatment and intolerant, unresponsive or recurring to one or more existing chemotherapy regimens. In a cohort comprising individuals in need of treatment for pancreatic cancer, administration of atezolizumab resulted in increased efficacy in the cohort compared to the case where atezolizumab was not administered.

In one form, the medicament of the present invention is a tocilizumab-containing medicament for treating pancreatic cancer without standard treatment and intolerant, unresponsive or recurring to one or more existing chemotherapy regimens, compared to In the case where tocilizumab was not administered, in a cohort comprising individuals in need of pancreatic cancer treatment, administration of tocilizumab resulted in increased efficacy in the cohort.

In one aspect, the treatment method of the present invention is a method for treating pancreatic cancer, comprising the steps of administering the medicine of the present invention to an individual according to each embodiment described in this specification. It can be a group of individuals without a treatment history of systemic therapy for metastatic pancreatic cancer, or it can be a group of individuals with a history of prior treatment with systemic therapy for one treatment of metastatic pancreatic cancer.

In one aspect, the treatment method of the present invention is a method for treating recurrent or treatment-resistant pancreatic cancer, comprising the steps of: administering the medicine of the present invention to an individual according to each embodiment described in this specification.

In one form, the treatment method of the present invention is a method for treating pancreatic cancer without standard treatment and intolerant, unresponsive or recurring to one or more existing chemotherapy regimens, comprising the steps of: In each of the described embodiments, the medicine of the present invention is administered to an individual.

In one form, the use of the present invention is the use of an anti-PD-L1 antibody, more specifically atezolizumab, for the manufacture of the medicament of the present invention. In one form, the use of the present invention is the use of an anti-IL-6R antibody, more specifically tocilizumab, for the manufacture of the medicament of the present invention.

Effects of IL-6 Inhibitors One aspect of the present invention is based on the newly discovered effects of IL-6 inhibitors. IL-6 inhibitors were found to promote the penetration of low molecular weight agents in target tissues. In addition, IL-6 inhibitors have the potential to inhibit target tissue fibrosis. Based on these effects, an IL-6 inhibitor can be used in the treatment of cancer of an individual using a cancer therapeutic agent in order to promote the penetration of the therapeutic agent into the cancer tissue. Therefore, it is preferable to administer the pharmaceutical composition containing an IL-6 inhibitor in combination with the above-mentioned therapeutic agent. The drug for the treatment of cancer is preferably a drug with a molecular weight of 400 or less. The therapeutic agent for cancer is more preferably a chemotherapeutic agent with a molecular weight of 400 or less. The cancer to be treated may be pancreatic cancer or lung cancer, but is not limited to these. The drug for cancer treatment can be gemcitabine and its pharmaceutically acceptable salts. The IL-6 inhibitor can be an anti-IL-6R antibody, such as tocilizumab.

Furthermore, another aspect of the present invention is also based on the effect of the newly discovered IL-6 inhibitor. Through experiments using anti-IL-6R antibodies, IL-6 inhibitors were found to promote the infiltration of immune cells (eg, CD45 positive cells) into target tissues. The aforementioned target tissue may be an IL-6 overexpressing tissue. In addition, the above-mentioned target tissue may be a collagen overproducing tissue. In addition, the target tissue may be a highly fibrous and/or tissue containing a relatively dense stroma (connective tissue hyperplasia). In addition, the above-mentioned target tissue may be a tumor tissue. Therefore, in order to promote the infiltration of CD45-positive cells into tumor tissue, IL-6 inhibitors can be used. The IL-6 inhibitor can be an anti-IL-6R antibody, such as tocilizumab. The tumor tissue may be pancreatic cancer or lung cancer tumor tissue, but is not limited to these.

In the present invention, the so-called "IL-6 overexpressing tissue" refers to a tissue in which the expression level of IL-6 is higher than that in the surrounding tissue or the tissue in the healthy normal control group. Examples of such tissues include chronic inflammatory states such as joint fluid of patients with chronic rheumatism, local inflammation, tumors, and the like. Cancer patients whose blood IL-6 concentration or blood CRP concentration is higher than the average blood concentration of healthy normal subjects can be defined as having "IL-6 overexpressing tumor tissue" in the body, but it is not limited to this.

Collagen is highly produced in the stroma of pancreatic cancer (PC), and the accumulation of collagen increases the fluid pressure in the tumor stroma, reducing blood flow and drug penetration. In the present invention, the so-called "collagen overproducing tissue" refers to a tissue that produces a higher amount of collagen than the surrounding tissue or the tissue of the healthy normal control group. Collagen includes type I collagen (C1), type II collagen (C2), type III collagen (C3), type IV collagen (C4), type VI collagen (C6), and other types of collagen. Pro-collagen peptide I (Pro-C1), pro-collagen peptide type II (Pro-C2), pro-collagen peptide type III (Pro-C3, Pro-C3X), pro-collagen peptide type I V (Pro-C3X) (Pro-C4), VI pro-collagen peptide (ProC-6). Cancer patients whose blood concentration of collagen is higher than the average blood concentration of healthy normal subjects can be defined as having "tumor tissue overproducing collagen" in the body, but it is not limited to this.

In the present invention, in tumor specimens collected from pancreatic cancer liver metastases of patients after administration of GN+anti-IL-6R antibody, it was observed that connective tissue hyperplasia was inhibited, and phosphorylation of STAT3, a factor downstream of IL-6 signaling, was obtained. Significant inhibition was observed, thereby confirming the effect of the anti-IL-6R antibody. From this result, it was confirmed that anti-IL-6R antibody + GN therapy induces superior inhibition of connective tissue proliferation compared with GN therapy, and exerts an antitumor effect. Therefore, one aspect of the present invention is based on improving the tumor microenvironment and promoting the penetration of drugs through the action of IL-6 inhibitor.

Therefore, one aspect of the present invention can be a group of individuals positive for phosphorylated STAT3. "Phosphorylated STAT3 positive" means that cells (for example, tumor cells, immune cells, and fibroblasts, but not limited to these) in the tumor tissue before administration have a high ratio of phosphorylated STAT3 positive areas. , more specifically, 1% or more and 100% or less, 5% or more and 100% or less, but not limited to these.

The so-called "promoting the penetration of low-molecular-weight drugs in vivo into IL-6-overexpressing tissues by IL-6 inhibitors" refers to promoting the penetration of drugs with molecular weights below 400 by IL-6 inhibitors in one form. Furthermore, in one form, the IL-6 inhibitor promotes the penetration of an agent having a molecular weight of 400 or less into the IL-6 overexpressing tissue. Furthermore, in one form, the penetration of agents with a molecular weight of 400 or less into tissues that are highly fibrous and/or contain a denser stroma (connective tissue hyperplasia) is facilitated by an IL-6 inhibitor. In the state of "highly fibrous and/or containing dense stroma", for example, HE-stained images of tumor fibrous stroma, or aggregation of α-SMA-positive cells were observed. The so-called "drugs with a molecular weight of 400 or less" include, for example, 5-fluorouracil (molecular weight 130.08), tegafur (200.16), gemcitabine (263.20), cisplatin (300.05), capecitabine (359.5), erlotite Ni (393.436), Oxaliplatin (397.29) and so on.

The so-called "promoting the infiltration of immune cells" means that the ratio of CD45-positive cells is higher in the case of administering the IL-6 inhibitor than in the case of not administering the IL-6 inhibitor. It is known that CD45, also known as leukocyte common antigen (LCA), B220, and T200, is a single-chain transmembrane protein tyrosine phosphatase expressed on the cell membrane of all hematopoietic cells except erythrocytes and platelets. CD45 characterizes human mesenchymal stem cells (MSCs) derived from bone marrow and other sources. "CD45 positive cells" are positive, including neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Lymphocytes include natural killer cells, T cells, and B cells.

Effect of Combined Use of IL-6 Inhibitor and Immune Checkpoint Inhibitor Furthermore, another aspect of the present invention is based on a newly discovered effect when an IL-6 inhibitor and an immune checkpoint inhibitor are used together. It was initially discovered that the infiltration of immune cells into target tissues is facilitated by the combination of IL-6 inhibitors and immune checkpoint inhibitors. Representative examples of immune cells may be CD45 positive cells and B cells. The target tissue may be an IL-6 overexpressing tissue. The target tissue can be tumor tissue. The tumor tissue may be pancreatic cancer or lung cancer tumor tissue, but is not limited to these. Representative examples of immune checkpoint inhibitors are those that bind to immune checkpoint molecules, such as those that bind to CTLA-4 (ie, CTLA-4 inhibitors), or those that bind to PD-1 or PD-L1 (ie, those that bind to PD-1 or PD-L1). PD-1/PD-L1 signaling inhibitor). The immune checkpoint inhibitor can be, for example, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, or any combination of these.

One aspect of the present invention is the combined use of IL-6 inhibitor and immune checkpoint inhibitor (such as PD-1/PD-L1 signaling inhibitor or CTLA-4 inhibitor) and other anti-tumor agents, through IL-6 signaling Inhibitors improve the tumor microenvironment, promote the penetration of drugs, and promote the infiltration of immune cells into tumor tissues through immune checkpoint inhibitors, thereby exerting excellent anti-tumor effects.

In one form, the present invention is a combination of an IL-6 inhibitor and an immune checkpoint inhibitor for use in immunotherapy-based concomitant therapy. One specific form is a combination of anti-IL-6R antibody and anti-PD-L1 antibody. In the present invention, it was confirmed that the combined use of anti-IL-6R antibody and anti-PD-L1 antibody significantly promoted the infiltration of major immune cells including T cells and neutrophils or monocytes into pancreatic cancer tumor tissue. Furthermore, an antitumor effect was actually confirmed by a test using a mouse pancreatic cancer model.

Furthermore, as a specific form, a combination of an anti-IL-6R antibody and a PD-L1 antibody is used in combination with at least one chemotherapeutic agent. In the present invention, by the combined administration of anti-IL-6R antibody + anti-PD-L1 antibody + gemcitabine, it was confirmed that the infiltration of CD45-positive immune cells represented by dendritic cells, T cells, and B cells into tumors was increased. , suggesting induction of acquired immunity. Therefore, it is considered that the combined administration of anti-IL-6R antibody + anti-PD-L1 antibody + chemotherapeutic agent enhances cancer by maintaining the infiltration of various immune cells in tumor tissue and inducing activation of T cells and B cells to generate acquired immunity Effects of immunotherapy.

Administration of Tocilizumab and / or Atezolizumab In one form, the medicament of the present invention is the administration of tocilizumab and/or atezolizumab for the treatment of pancreatic cancer in an individual of medicine.

The medicine of the present invention may be a therapeutic agent for pancreatic cancer containing tocilizumab or atezolizumab administered in combination with tocilizumab. Alternatively, the medicine of the present invention may be a therapeutic agent for pancreatic cancer containing atezolizumab or tocilizumab administered in combination with atezolizumab. Pancreatic cancer may be pancreatic cancer that is resistant to chemotherapeutic agents.

The present invention is characterized in that the above-mentioned medicine for improving the effectiveness in a group including individuals requiring treatment of pancreatic cancer resistant to a chemotherapeutic agent includes, in one embodiment, a need for treatment with a chemotherapeutic agent The cohort of individuals treated for drug-resistant cancer may also include individuals who have not been diagnostically tested for drug resistance prior to administration of tocilizumab and/or atezolizumab. Or with regard to the medicine, in another embodiment, a group comprising individuals in need of treatment for cancers resistant to chemotherapeutic agents may also be included in the administration of tocilizumab and/or atezolizumab Individuals identified as drug-resistant by prior diagnostic testing for drug resistance.

In one form, the treatment method of the present invention is a treatment method for pancreatic cancer resistant to chemotherapeutic agents. In one embodiment, in a group comprising individuals in need of treatment for chemotherapeutic agent-resistant pancreatic cancer, compared to the situation where tocilizumab and/or atezolizumab were not administered , the treatment method increases the efficiency in the group.

The present invention is characterized in that the above-mentioned medicine for improving the effectiveness in a group including individuals requiring treatment of pancreatic cancer resistant to a chemotherapeutic agent includes, in one embodiment, a need for treatment with a chemotherapeutic agent The cohort of individuals treated for drug-resistant cancer may also include individuals who have not been diagnostically tested for drug resistance prior to administration of tocilizumab and/or atezolizumab. Or with regard to the medicine, in another embodiment, a group including individuals who need to undergo treatment for cancers resistant to chemotherapeutic agents may also be included in a diagnostic test for drug resistance prior to administration of tocilizumab to determine the presence or absence of drug resistance. drug-resistant individuals.

In one form, the use of the present invention is the use of tocilizumab and/or atezolizumab for the manufacture of the medicament or kit of the present invention. In the use of the present invention, a medicament or kit is a medicament or kit for treating pancreatic cancer in an individual. In this use, the pancreatic cancer is preferably recurrent/treatment resistant pancreatic cancer.

For the purposes of the present invention, a medicament or kit is a medicament or kit for treating pancreatic cancer resistant to chemotherapeutic agents in an individual. For this use, in one embodiment, the medicament or kit comprises tocilizumab and/or atezolizumab.

In the use of the present invention, a medicament or kit is a medicament or kit for treating cancers that are resistant to chemotherapeutic agents. In one embodiment, the medicament or kit comprises tocilizumab and/or atezolizumab. In one embodiment, in a group comprising individuals in need of treatment for chemotherapeutic agent-resistant cancers, compared to when tocilizumab and/or atezolizumab were not administered, The medicine or kit increases the effectiveness in the group.

The above-mentioned use of the present invention is characterized by increasing the effectiveness in a group comprising individuals in need of treatment of chemotherapeutic agent-resistant cancers, in one embodiment, including the need for chemotherapeutic-agent-resistant cancers. The group of individuals for the treatment of cancer may also include individuals who have not been diagnostically tested for drug resistance prior to administration of the chemotherapeutic agent. Or with regard to the medicine or kit, in another embodiment, a group comprising individuals in need of treatment of chemotherapeutic agent-resistant cancers may also be included in diagnostic testing for drug resistance prior to administration of the chemotherapeutic agent. Identify drug-resistant individuals. Also, in another embodiment, the drug resistance may be drug resistance caused by prior treatment including chemotherapy.

In addition to tocilizumab and/or atezolizumab, the medicine and kit of the present invention can also be used in combination with other medicines for treating pancreatic cancer, or known treatments such as radiation therapy or surgery. .

The medicine and kit of the present invention include an embodiment of the medicine or kit prepared by formulating tocilizumab and/or atezolizumab as active ingredients. The treatment method of the present invention is a treatment method for treating pancreatic cancer in an individual in need thereof. It includes the following steps: according to each embodiment described in this specification, the medicine, the kit of the present invention, and tocilizumab and/or atezolizumab are administered to the individual.

The treatment method of the present invention may also include: using the medicines, kits of the present invention, and other medicines, pharmaceuticals or drugs other than tocilizumab and/or atezolizumab for treating cancer as specifically described in this specification. Procedures for treatment such as kits, or procedures for performing known treatments such as radiation therapy or surgery. Other medicines may contain one or more chemotherapeutic agents.

The use of the present invention is the use of tocilizumab and/or atezolizumab for the manufacture of the medicine or kit of the present invention. In addition to the use of tocilizumab and/or atezolizumab, the use of the present invention may also include the use of other drugs for treating cancer, or known treatments such as radiation therapy or surgery. Other agents may contain one or more chemotherapeutic agents.

The tocilizumab and/or atezolizumab of the present invention can also be used in combination with other medicines, pharmaceuticals, kits, etc. for treating pancreatic cancer, or known treatments such as radiation therapy or surgery.

By administering tocilizumab and/or atezolizumab to individuals with pancreatic cancer, compared to the situation where tocilizumab and/or atezolizumab were not administered High effect.

As an aspect of the present invention, a group of individuals with higher C-reactive protein (CRP) is selected. The so-called "high C-reactive protein", more specifically, the concentration in serum or plasma is 0.5 mg/dL or more and less than 10 mg/dL, 1 mg/dL or more and less than 10 mg/dL, 2 mg/dL Above and below 10 mg/dL, above 3 mg/dL and below 10 mg/dL, above 4 mg/dL and below 10 mg/dL, above 5 mg/dL and below 10 mg/dL, 7 mg /dL or more and less than 10 mg/dL of individual groups, but not limited to these.

Furthermore, when tocilizumab and/or atezolizumab were used for chemotherapy-unresponsive pancreatic cancer, it was confirmed that tocilizumab and/or atezolizumab were not used. In this case, the anticancer effect is high. Therefore, the medicine and the like of the present invention are particularly effective in the treatment of difficult-to-treat pancreatic cancer that is not responsive to chemotherapy.

Therefore, in a group including individuals in need of cancer treatment, by using the medicine of the present invention, etc. to treat pancreatic cancer, compared with a control group without such treatment, each individual in the group obtained Higher anticancer effect. Here, the control group may be a group comprising individuals in need of pancreatic cancer treatment and not administered tocilizumab.

For example, in the case where the medicament of the present invention is a medicament containing tocilizumab and/or atezolizumab, in a group comprising individuals in need of pancreatic cancer treatment, compared with In the absence of administration of tocilizumab and/or atezolizumab, higher anticancer effects were obtained in each individual in the group.

As described above, by treating with tocilizumab and/or atezolizumab, the medicament of the present invention and the like are also effective for chemotherapy-unresponsive cancers. Therefore, in the case where the above-mentioned group is a group of individuals suffering from chemotherapy-unresponsive cancer, the medicines and the like of the present invention are particularly effective. When the medicament and the like of the present invention are used in a group including individuals with chemotherapy-unresponsive cancer, compared to the case in which tocilizumab and/or atezolizumab are not used, an increase in The ratio of individuals who confirmed the anticancer effect, that is, the effective rate was improved. In addition, the anergy is not particularly limited as long as it is not responsive to chemotherapy or has drug resistance, and may be innate drug resistance, acquired drug resistance, or anergy in recurrent pancreatic cancer. In one embodiment, the group comprising individuals in need of treatment for pancreatic cancer comprises individuals determined to be drug-resistant. In another embodiment, the group comprising individuals in need of treatment for pancreatic cancer includes individuals determined to have acquired resistance due to prior treatment. In this embodiment, for example, the medicine may be a medicine containing tocilizumab and/or atezolizumab.

In one embodiment, the group comprising individuals in need of treatment for pancreatic cancer may be comprised of individuals who have not been identified prior to treatment with tocilizumab and/or atezolizumab for the absence of chemotherapy for pancreatic cancer. Groups of reactive individuals. In one embodiment, for at least a portion of the group including individuals in need of pancreatic cancer treatment, the pancreatic cancer can be identified before treatment with tocilizumab and/or atezolizumab. Whether the cancer is unresponsive to chemotherapy. Anergy is not particularly limited as long as it is unresponsive to chemotherapy or has drug resistance, and it may be innate drug resistance. As described above, in the case of cancer that is not responsive to chemotherapy, the medicine of the present invention is particularly effective, and therefore, the effectiveness in a group including individuals requiring pancreatic cancer treatment can be particularly improved. .

By using tocilizumab and/or atezolizumab, the medicine of the present invention has no reactivity to chemotherapy compared to the case where tocilizumab and/or atezolizumab are not used. Pancreatic cancer or responsive cancer, both play a significantly higher anticancer effect. However, because of its effectiveness especially in the treatment of refractory pancreatic cancer that is not responsive to chemotherapy, it is not suitable to continue the previously treated pancreas for individuals who are resistant or non-responsive to the previous treatment. Cancer, or pancreatic cancer with an unexpected degree of responsiveness to prior treatment (eg, non-responsiveness, and/or cause of toxicity), i.e., pancreatic cancer with innate resistance to chemotherapeutic agents, or with It is particularly effective in the treatment of difficult-to-treat pancreatic cancer such as pancreatic cancer that has acquired resistance after previous treatment with chemotherapy or the like, or recurrent pancreatic cancer that has appeared after previous treatment with chemotherapy or the like. The medicine and the like of the present invention are particularly effective for cancers that are difficult to treat because they are unresponsive to chemotherapy. Even for pancreatic cancer that is not responsive to chemotherapy, i.e., pancreatic cancer that is innately resistant to chemotherapeutic agents, or that is acquired resistance due to previous treatments that have been performed, or that has recurred Cancer, tocilizumab and/or atezolizumab exerted a higher effect than the case where tocilizumab and/or atezolizumab were not administered, significantly improving the therapeutic effect of cancer.

In addition, the medicament and the like of the present invention can be used to treat, for example, pancreatic cancer that cannot be surgically removed, that has advanced and/or recurred. The medicament and the like of the present invention can be preferably used for the treatment of advanced or recurrent pancreatic cancer that does not require curative resection, unresectable advanced or recurrent pancreatic cancer, or inoperable or recurrent pancreatic cancer.

In one embodiment of the present invention, the pancreatic cancer to be treated in the medicine or the like of the present invention may be pancreatic cancer that is still progressing at the time of previous treatment, during treatment, or after treatment. For example, the cancer may be pancreatic cancer that is still progressing after previous treatment. For example, it may be pancreatic cancer that is still progressing for a period of time within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months after the start of the previous treatment. In another embodiment, for example, it may be pancreatic cancer that is still progressing after a period of about 3, 6, 9, or 12 months from the beginning of the previous treatment. In one embodiment of the present invention, the pancreatic cancer is drug-resistant or non-responsive to previous treatments. In another embodiment, the pancreatic cancer is recurrent. That is, pancreatic cancer is initially responsive to treatment with the previous treatment, but after the previous treatment is discontinued, after a certain period of about 6, 7, 8, 9, 10, 11, 12, 24 or 36 months, the cancer becomes Primary tumor recurrence, or metastatic recurrence.

Standard therapy + IL-6 inhibitor and / or PD-1/PD-L1 signaling inhibitor The present invention provides an IL-6 inhibitor and PD-1/PD in addition to standard therapy using at least one chemotherapeutic agent - Therapy with either one or a combination of L1 signaling inhibitors.

The present invention provides a pharmaceutical composition or kit containing an anti-IL-6R antibody and an anti-PD-L1 antibody for enhancing the effect of a chemotherapeutic agent in pancreatic cancer chemotherapy.

In the above pharmaceutical composition or set, pancreatic cancer is pancreatic cancer with innate resistance to chemotherapeutic agents or acquired resistance to chemotherapeutic agents, characterized by combining the chemotherapeutic agents with anti-IL-6R Antibody and anti-PD-L1 antibody were used in combination to improve the effectiveness of the administration group.

Furthermore, the present invention provides a pharmaceutical composition or kit containing an anti-IL-6R antibody and an anti-PD-L1 antibody for treating pancreatic cancer in an individual who needs treatment for pancreatic cancer that has recurred after administration of a chemotherapeutic agent .

Method of Administration The dosage and schedule of administration of the medicine of the present invention vary according to the subject to be administered, the subject's age, weight, disease state, and the method of administration. Certainly. For example, in the time difference administration plan, it can be administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 8 hours before the effective dose of the second medicine is administered. , 9 hours, 10 hours, 11 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 8 days ago, administer an effective amount of First Medicine. Furthermore, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, Administer an effective amount of the second medicine 10 hours ago, 11 hours ago, 1 day ago, 2 days ago, 3 days ago, 4 days ago, 5 days ago, 6 days ago, 7 days ago, or 8 days ago. Furthermore, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, Administer an effective amount of the third medicine 10 hours ago, 11 hours ago, 1 day ago, 2 days ago, 3 days ago, 4 days ago, 5 days ago, 6 days ago, 7 days ago or 8 days ago.

As a non-limiting example, for the purpose of treating a person diagnosed with pancreatic cancer, the IL-6 inhibitor is tocilizumab, and the PD-1/PD-L1 signaling inhibitor is atezolizumab The dosage and administration interval of the medicine of the present invention in this case will be described.

The usual dose of tocilizumab can be, for example, according to the route of administration, about 10 ng/kg to about 100 mg/kg (body weight) per day on average, preferably about 1 mg/kg/day to 10 mg/kg Changes within the range of /day. For example, the dosage of tocilizumab can be about 0.1-100 mg/kg/week or the dosage showing the same blood concentration, preferably 1-50 mg/kg/week or the dosage showing the same blood concentration The dosage is more preferably 5-10 mg/kg/week or the dosage showing the same blood concentration. The number of injections may be one type of injection or a plurality of different types of injection. For example, a fixed amount or a variable amount may be administered at intervals of 1 week, 2 weeks, 3 weeks, or 4 weeks, depending on the state of the patient to be administered. Alternatively, a fixed amount may be administered by shortening or extending the administration interval depending on the state of the patient to be administered.

For example, in the case of intravenous administration, a fixed amount or a variable amount may be administered at intervals of 1 week, 2 weeks, 3 weeks, or 4 weeks, depending on the state of the patient to be administered. For example, in the case of intravenous drip, as tocilizumab (gene recombination), 2-24 mg/kg can be administered once every 2-4 weeks. For example, 4 mg/kg once with 2-week interval (Q2W) or 3-week interval (Q3W) or 4-week interval (Q4W) or 8 mg/kg once with 2-week interval (Q2W) or 3-week interval (Q3W) ) or at 4-week intervals (Q4W), tocilizumab was administered via intravenous infusion. The so-called "dose of 4 mg/kg once with a 2-week interval (Q2W)" refers to 4 mg as a unit dose per 1 kg of the body weight of the administered subject, administered once every 2 weeks. That is, when the first administration day is set as the first day, the next administration is performed on the 15th day. In the case of subcutaneous administration, for example, as tocilizumab (gene recombination), 20-350 mg, preferably 50-250 mg, more preferably 80-200 mg can be subcutaneously injected once, every 1-4 Inject once a week.

The dosage of atezolizumab can be about 10 ng/kg to about 100 mg/kg (body weight), preferably about 1 mg/kg/day to 50 mg/day, on average, depending on the route of administration. Changes within the range of kg/day. For example, a single dose of atezolizumab may range from about 500 to 2000 mg. The number of injections depends on the injection route, and one type of injection or a plurality of different types of injection may be used.

For example, in the case of intravenous administration, a fixed amount or a variable amount may be administered at intervals of 1 week, 2 weeks, 3 weeks, or 4 weeks, depending on the state of the patient to be administered. For example, in the case of intravenous drip, as atezolizumab (gene recombination), 50-2000 mg can be administered once every 2-4 weeks. For example, atezolizumab can be administered at a dose of 840 mg once with a 2-week interval (Q2W) or 1200 mg once with a 3-week interval (Q3W) or 1680 mg once with a 4-week interval (Q4W) . In the case of "840 mg once with a 2-week interval" or "840 mg once with a 2-week interval", regardless of body weight, 840 mg is administered once, and the first administration day is set as the first day , the next dose was on the 15th day. For example, in the case of intravenous infusion of atezolizumab at a 3-week interval (Q3W) at 1,200 mg once, the dose can be set as follows: 1,200 mg once every 60 minutes, every 3 weeks Give once.

As a form, 2 to 4 weeks can be used as an Period, according to the following doses administered.・Intravenous infusion of tocilizumab 2～10 mg/kg on the first day of each cycle; ・Intravenous infusion of atezolizumab 400～2400 mg on the first day of each cycle; ・In each cycle, Nab-paclitaxel and gemcitabine hydrochloride were administered in multiple doses according to the dose and interval of administration according to standard therapy. With regard to gemcitabine hydrochloride, for example, for adults, 1000 mg/m ² (body surface area) or 750 mg/m ² (body surface area) once, as an intravenous infusion over 30 minutes, administered once a week, continuously administered Give 3 weeks and stop at week 4. It can be implemented iteratively as an administration process. Furthermore, the dosage should be appropriately reduced according to the patient's condition. Also, with regard to albumin-bound paclitaxel, for example, for adults, 125 mg/m ² (body surface area) once a day or 100 mg/m ² (body surface area) once a day is administered intravenously over 30 minutes, every time It was administered once a week for 3 consecutive weeks, and the drug was discontinued in the 4th week. It can be implemented iteratively as an administration process. Furthermore, the dosage should be appropriately reduced according to the patient's condition.

As a form, in the case of combining a drug containing atezolizumab with tocilizumab, gemcitabine, and nab-paclitaxel for the treatment of pancreatic cancer in a human subject, it can be treated by including: The method of the operation of the individual to perform the administration uses: (i) The dose of tocilizumab is 8 mg/kg once with a 4-week interval (Q4W); and the dose of atezolizumab is selected from 840 mg once with a 2-week interval (Q2W), 1200 mg once mg with a 3-week interval (Q3W) and 1680 mg once with a 4-week interval (Q4W); or (ii) The dose of tocilizumab is 4 mg/kg once with 2 weeks interval (Q2W); and the dose of atezolizumab is selected from 840 mg once with 2 weeks interval (Q2W), 1200 mg once mg at 3-week intervals (Q3W), 1680 mg once at 4-week intervals (Q4W), or administered to human subjects at the following doses: (iii) The dose of tocilizumab is 8 mg/kg once with 2 weeks interval (Q2W); and the dose of atezolizumab is selected from 840 mg once with 2 weeks interval (Q2W), 1200 mg once mg with a 3-week interval (Q3W) and 1680 mg once with a 4-week interval (Q4W).

Furthermore, nab-paclitaxel and gemcitabine hydrochloride can be administered in combination according to standard therapy. That is, the administration of nab-paclitaxel and gemcitabine hydrochloride can be combined with the usage and dosage of any of the above-mentioned tocilizumab and the usage and dosage of atezolizumab. For example, the following dosages can be administered to a subject human subject: (iv) tocilizumab at a dose of 8 mg/kg once at 4-week intervals (Q4W); and atezolizumab at a dose of 1 1680 mg once a week with an interval of 4 weeks (Q4W); and once a week for 3 consecutive weeks, nab-paclitaxel and gemcitabine hydrochloride, discontinued in the 4th week, and the dose of nab-paclitaxel is 125 mg/m ² once per paclitaxel (body surface area), the dose of gemcitabine hydrochloride is calculated as 1000 mg/m ² (body surface area) once with gemcitabine.

As a form, in the case of combining a medicine containing tocilizumab with atezolizumab, gemcitabine, and nab-paclitaxel for the treatment of cancer in a human subject, the following doses may be administered to the subject human subject Throw in: (i) The dose of tocilizumab is 8 mg/kg once with a 4-week interval (Q4W); and the dose of atezolizumab is selected from 840 mg once with a 2-week interval (Q2W), once A cohort of 1200 mg at 3-week intervals (Q3W) and 1680 mg once at 4-week intervals (Q4W); or (ii) the dose of tocilizumab is 4 mg/kg once with a 4-week interval (Q4W); and the dose of atezolizumab is selected from 840 mg once with a 2-week interval (Q2W), once A group consisting of 1200 mg at 3-week intervals (Q3W) and 1680 mg once at 4-week intervals (Q4W); (iii) the dose of tocilizumab is 8 mg/kg once with a 2-week interval (Q2W); and the dose of atezolizumab is selected from 840 mg once with a 2-week interval (Q2W), once A group consisting of 1200 mg at 3-week intervals (Q3W) and 1680 mg once at 4-week intervals (Q4W).

Furthermore, nab-paclitaxel and gemcitabine hydrochloride can be administered in combination according to standard therapy. That is, the administration of nab-paclitaxel and gemcitabine hydrochloride can be combined with the usage and dosage of any of the above-mentioned tocilizumab and the usage and dosage of atezolizumab. For example, the following dosages can be administered to a subject human subject: (iv) tocilizumab at a dose of 8 mg/kg once at 4-week intervals (Q4W); and atezolizumab at a dose of 1 1680 mg once a week with an interval of 4 weeks (Q4W); and once a week for 3 consecutive weeks, nab-paclitaxel and gemcitabine hydrochloride, discontinued in the 4th week, and the dose of nab-paclitaxel is 125 mg/m ² once per paclitaxel (body surface area), the dose of gemcitabine hydrochloride is calculated as 1000 mg/m ² (body surface area) once with gemcitabine.

As a modality, 28 days (4 weeks) of atezolizumab-containing medicine in combination with tocilizumab, gemcitabine, and nab-paclitaxel for the treatment of pancreatic cancer in human subjects As a cycle, the following doses are administered.・Intravenous tocilizumab 4 mg/kg or 8 mg/kg on day 1 of each cycle; ・Intravenous infusion of atezolizumab 1200 mg or 1680 mg on day 1 of each cycle; here , atezolizumab may be administered several hours after the end of the intravenous infusion of tocilizumab (eg, after about 2 hours, after about 3 hours, after about 4 hours).・Intravenous infusion of 125 mg/m ² of nab-paclitaxel based on paclitaxel on days 1, 8 and 15 of each cycle (after the end of the infusion of atezolizumab on day 1 of each cycle); ・In each cycle On days 1, 8 and 15 of the cycle (after the end of the infusion of nab-paclitaxel on day 1 of each cycle), 1000 mg/m ² of gemcitabine hydrochloride was infused intravenously.

As a form, in the case of combining atezolizumab-containing medicines with tocilizumab, gemcitabine, and nab-paclitaxel for the treatment of pancreatic cancer in human subjects, 21 days (3 weeks) As a cycle, the following doses are administered.・Intravenous tocilizumab 4 mg/kg or 8 mg/kg on day 1 of each cycle; ・Intravenous infusion of atezolizumab 840 mg or 1200 mg on day 1 of each cycle; here , atezolizumab may be administered several hours after the end of the intravenous infusion of tocilizumab (eg, after about 2 hours, after about 3 hours, after about 4 hours).・Intravenous infusion of 125 mg/m ² of nab-paclitaxel based on paclitaxel on days 1, 8 and 15 of each cycle (after the end of the infusion of atezolizumab on day 1 of each cycle); ・In each cycle On days 1, 8 and 15 of the cycle (after the end of the infusion of nab-paclitaxel on day 1 of each cycle), 1000 mg/m ² of gemcitabine hydrochloride was infused intravenously.

As a form, 14 days (2 weeks) can be used in the case of combining a medicine containing atezolizumab with tocilizumab, gemcitabine, and nab-paclitaxel for the treatment of pancreatic cancer in a human subject. As a cycle, the following doses are administered.・Intravenous infusion of tocilizumab 4 mg/kg or 8 mg/kg on day 1 of each cycle; ・Intravenous infusion of atezolizumab 840 mg on day 1 of each cycle; Atezolizumab is administered several hours after the end of the intravenous infusion of tocilizumab (eg, after about 2 hours, after about 3 hours, after about 4 hours).・Intravenous infusion of 125 mg/m ² of nab-paclitaxel based on paclitaxel on Days 1 and 8 of each cycle (after the end of atezolizumab infusion on Day 1 of each cycle); On days 1 and 8 (after the end of the infusion of nab-paclitaxel on day 1 of each cycle), 1000 mg/m ² of gemcitabine hydrochloride based on gemcitabine was administered intravenously.

As another example, the use of tocilizumab for the treatment of chemotherapeutic agent-resistant cancer, or for promoting the penetration of chemotherapeutic agents into cancer tissues, or for promoting the infiltration of CD45-positive cells into target tissues, will be described. .

In one form, the drug containing tocilizumab is administered in combination with a chemotherapeutic agent in the treatment of cancer to enhance the effect of the chemotherapeutic agent, preferably the chemotherapeutic agent and the IL-6 inhibitor are simultaneously administered Dosing, separate dosing, or continuous dosing.

In one form, the drug containing tocilizumab is used for the treatment of chemotherapeutic-resistant cancers, preferably in a group comprising individuals in need of treatment of chemotherapeutic-resistant cancers ( patient population), the remission rate or disease control rate in the cohort was improved compared to the case where the chemotherapeutic agent was administered without tocilizumab.

In one form, the medicine containing tocilizumab is used in combination with or in combination with a chemotherapeutic agent to treat cancer resistant to the chemotherapeutic agent, and the chemotherapeutic agent and tocilizumab are administered simultaneously , separate administration, or continuous administration.

In the above case, it is preferable to increase the number of patients in the group including the individual in need of treatment of cancer resistant to the chemotherapeutic agent compared to the case where the chemotherapeutic agent is administered without tocilizumab. rate of remission or disease control.

In the above situation, (a) the aforementioned group comprising individuals in need of treatment of chemotherapeutic-resistant cancers comprises individuals who were not tested for resistance by diagnosis prior to administration of the chemotherapeutic agent; or (b) the above-mentioned cancer that is resistant to a chemotherapeutic agent may be a cancer that is innately resistant to a chemotherapeutic agent; or (c) the above-mentioned cancers that are resistant to chemotherapeutic agents may be cancers that have acquired resistance to chemotherapeutic agents; or (d) The above-mentioned cancer resistant to a chemotherapeutic agent may be a cancer that recurs after administration of the chemotherapeutic agent.

In the above case, the usual dose of tocilizumab depends on, for example, the route of administration, and can range from about 10 ng/kg to about 100 mg/kg (body weight) per day, preferably about 1 mg/kg/day. Varies within the range of ~10 mg/kg/day. For example, the dosage of tocilizumab can be about 0.1-100 mg/kg/week or the dosage showing the same blood concentration, preferably 1-50 mg/kg/week or the dosage showing the same blood concentration The dosage is more preferably 5-10 mg/kg/week or the dosage showing the same blood concentration. The number of injections may be one type of injection or a plurality of different types of injection. For example, a fixed amount or a variable amount may be administered at intervals of 1 week, 2 weeks, 3 weeks, or 4 weeks, depending on the state of the patient to be administered. Alternatively, a fixed amount may be administered by shortening or extending the administration interval depending on the state of the patient to be administered.

For example, in the case of intravenous drip, as tocilizumab (gene recombination), 4-12 mg/kg can be administered once every 2-4 weeks. For example, the dosage of tocilizumab can be 4 mg/kg once with 2-week interval (Q2W) or 3-week interval (Q3W) or 4-week interval (Q4W) or 8 mg/kg once with 2-week interval Weekly (Q2W) or 3-weekly (Q3W) or 4-weekly (Q4W) doses are administered by intravenous infusion. For example, in the case of subcutaneous administration, as tocilizumab (gene recombination), 162 mg can be administered subcutaneously once every 1 to 2 weeks.

Also, tocilizumab can be administered, for example, via intravenous infusion, for a human subject, in an administration amount of about 0.1 mg to about 30,000 mg per administration, more specifically, about 1 mg or more and about 1 mg per administration. 10 mg or less, about 80 mg or less, about 240 mg or less, about 840 mg or less, about 1,000 mg or less, or about 1,200 mg or less, more specifically, about 10 mg, about 80 mg, about 240 mg, About 840 mg or about 1,200 mg. Or more than about 1.0 mg/kg (body weight), about 2.0 mg/kg (body weight) or more, about 2.5 mg/kg (body weight) or more, about 10 mg/kg (body weight) or more, or about 20 mg/kg (body weight) or more per administration. kg (body weight) or more and about 100 mg/kg (body weight) or less, more specifically, about 2 mg/kg (body weight), about 10 mg/kg (body weight), about 15 mg/kg (body weight) can be administered each time ) or about 20 mg/kg (body weight). In addition, these doses can be administered, for example, once every about 2 weeks or more, or once every about 3 weeks or more. In addition, the injection time of each injection is not limited within the range of ensuring safe injection, and it is preferably about 30 minutes to about 90 minutes.

As mentioned above, the manufacturer can determine the dosage and schedule of tocilizumab according to the embodiment. For human subjects, the dosage for each administration is about 1,200 mg, which can be administered at intervals of about 1 to 4 weeks. It is administered once, preferably every about 2 to 3 weeks.

Regarding the administration of tocilizumab, the manufacturer can appropriately adjust the administration time, administration interval, administration frequency, and administration period according to the therapeutic effect, the patient's condition, and tolerance. In the medicine and the like of the present invention, tocilizumab can also be administered in combination with one or more chemotherapeutic agents. In this case, the practitioner can appropriately adjust the administration time, administration interval, administration frequency, and administration period of tocilizumab and one or more chemotherapeutic agents according to the therapeutic effect, the patient's condition, tolerance, etc. .

EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.

The criteria and definitions used in the present invention are as follows. Disease classification criteria Stage classification (Staging) is based on the stage classification of malignant exocrine pancreatic tumors of the "UICC-TNM 8th Edition".

[Table 1] Disease classification content IA Cancer with a length of 2 cm or less IB Cancer with a long diameter of 2 cm or more and less than 4 cm IIA Cancer with a length of 4 cm or more IIB No distant metastases, but the number of metastases to the associated lymph nodes is 1 to 3 III No distant metastasis, but the number of metastases to the associated lymph node is 1 to 3, or the cancer has infiltrated into the celiac artery, superior mesenteric artery, or common hepatic artery IV have distant metastases

Daily Performance Status (ECOG (Eastern Cooperative Oncology Group, East Coast Cancer Clinical Research Collaborative) classification) The Japanese version of ECOG's Daily Performance Status (39) is cited from the JCOG (Japan Clinical Oncology Group) web page (http://www.jcog.jp/).

[Table 2] PS content 0 There is absolutely no problem with the activity. As before the onset of the disease, the conduct of daily life is not affected. 1 Vigorous exercise is affected, but is able to walk and perform lighter tasks or tasks that do not require standing. such as simple housework, office 2 Able to move around and take care of herself completely, but unable to work. More than 50% of the day is spent outside the bed. 3 Part of life takes care of itself. More than 50% of the day is spent in bed or chair. 4 Completely inactive. Life is completely out of control. Spend the day in bed or in a chair.

The Japanese version of Karonofsky performance status (40) is cited from the Guidelines for the Diagnosis and Treatment of Brain Tumors (https://www.jsn-o.com/guideline2016/index.html).

[table 3] 100% normal, no clinical symptoms 90% Mild clinical symptoms but able to function normally 80% Have obvious clinical symptoms, barely able to perform normal activities 70% Able to take care of themselves, but unable to perform normal activities and work 60% Has basic self-care skills, but often requires intervention 50% Nursing care and periodic medical actions may be required depending on the condition 40% Inability to move, requiring appropriate medical and nursing care 30% Completely immobile, requiring hospitalization, but not dying soon 20% Very serious condition requiring hospitalization and aggressive treatment 10% near death 0% die

The event name and grade (Grade) of adverse events adopt "Common Terminology Criteria for Adverse Events (CTCAE) v4.0-JCOG) [corresponding to CTCAE v4.03/MedDRA v12. 0]".

The tumor shrinkage effect was determined using the "New Response Evaluation Criteria for Solid Cancers (RECIST Criteria) Rev. 1.1-Japanese JCOG version-: Revised RECIST guideline (version 1.1)".

The following is an excerpt from the "New Response Evaluation Criteria in Solid Cancers (RECIST Criteria) Rev. 1.1-Japanese JCOG Edition-: Revised RECIST guideline (version 1.1)".

1. Baseline assessment According to the examination schedule, the tumor lesions before enrollment were identified by chest-abdominal and pelvic angiography CT or abdominal and pelvic angiography MRI, and various lesions were divided into "measurable lesions" and "unmeasurable lesions". The tumor diameter was measured using the cross-section images of CT or MRI, not the sagittal or coronal slices based on the three-dimensional reconstruction images. Baseline assessments were performed using the most recent image examination within 14 days prior to enrollment. After enrollment, the latest image examination of the re-examination shall be used in the case of re-examination of images before the start of treatment.

2. Definition of measurable lesions A lesion meeting any of the following is a measurable lesion.

1) Diseases other than lymph node disease (non-lymph node disease) that meet any of the following conditions ①The maximum diameter measured by CT or MRI with a slice thickness of less than 5 mm is more than 10 mm ② The maximum diameter measured by CT or MRI with slice thickness exceeding 5 mm is more than 2 times the slice thickness ③Osteolytic bone metastases with soft tissue components satisfying ① or ② ④ Cystic metastatic lesions satisfying ① or ② when there are no other measurable non-cystic lesions

2) Lymph node lesions with a short diameter of more than 15 mm measured by CT with a slice thickness of less than 5 mm (lymph node lesions with a short diameter of more than 10 mm and less than 15 mm are non-target lesions, and lymph nodes with a short diameter of less than 10 mm) not a disease)

3) The maximum diameter measured by the pure X-ray of the chest is more than 20 mm, and the surrounding is surrounded by lung fields (without touching the mediastinum or chest wall) 4) Clinical lesions (superficial skin lesions, etc.) with a maximum diameter of 10 mm or more can be photographed in measurable and color photographs

All lesions other than the above were classified as non-measurable lesions. Please note that the following lesions are not measurable lesions regardless of the examination method or the size of the lesions. ・Bone lesions (excluding osteolytic lesions with measurable soft tissue components) ・Cystic lesions (except 1)-4) above) ・ Lesions with a history of local treatment such as radiation therapy ・Pial lesions ・Abdominal cavity, pleural cavity, pericardial effusion ・Lymphangiopathy of the skin or lungs ・Abdominal tumors or enlargement of abdominal organs that are palpable but not detectable by imaging methods

3. Selection of target lesions and baseline recording When entering the group, select the confirmed measurable lesions (non-lymph node lesions: long diameter, lymph node lesions: short diameter) ranked in the top 5, and select at most 2 locations on each organ as target lesions (target lesion). When selecting, all organs with measurable lesions should be included as much as possible, and the reproducibility during repeated measurement, that is, reproducible repeated measurement, should be considered for selection (avoid selecting lesions with larger diameters that are difficult to measure).

For the selected target lesions, record on the CRF in order from cephalad to caudal: site, examination method, examination day, long diameter of non-lymph node target lesions, short diameter of lymph node target lesions, and all target lesions The sum of the diameters and lengths of (hereinafter referred to as the sum of diameters).

4. Baseline records of non-target lesions For the lesions that are not selected as target lesions, regardless of whether they can be measured or not, they are all regarded as non-target lesions, and the location of the lesions, the inspection method, and the inspection date are recorded on the CRF. Multiple non-target lesions in the same organ can be recorded as one lesion (eg, multiple enlarged pelvic lymph nodes, multiple liver metastases).

5. Determination of tumor shrinkage effect Target lesions and non-target lesions were evaluated by the same examination method as in the group, and the diameter of target lesions and the disappearance or deterioration of non-target lesions were recorded on CRF.

6. Efficacy criteria for target lesions ・CR (Complete Response): Complete remission All non-lymph node target lesions disappeared, and the short diameter of all lymph node target lesions did not reach 10 mm. In the case where the target lesion of the lymph node is selected based on the baseline, there are cases where the effect of the target lesion is CR even if the sum of diameters does not become 0 mm. ・PR (Partial Response): Partial mitigation Target lesion diameter and baseline diameter sum reduced by more than 30% ・PD (Progressive Disease): Disease progression For some reasons, the minimum diameter sum in the process cannot be checked (if the baseline is the minimum value in the process, it is regarded as the minimum diameter sum), or it cannot be determined as any of CR, PR, PD, SD. the situation The reduction ratio of the sum of diameters = (sum of diameters before treatment - sum of diameters at the time of evaluation)/(sum of diameters before treatment) × 100% The increase ratio of the diameter sum = (the diameter sum at the time of evaluation - the smallest diameter sum)/(the smallest diameter sum) × 100%

※As long as it can be measured (for example, even if it is less than 5 mm), the diameter and length of the target lesion shall be recorded as the measured value. Thickness is irrelevant, and the diameter is 0 mm when it is judged that there is no residual tumor lesion, and the diameter is 5 mm when it is judged that there is a residual tumor lesion. ※When the reduction ratio satisfies the conditions of PR and the enlargement ratio satisfies the conditions of PD at the same time, it is judged as PD. ※In the case of separation of one lesion during the treatment, add up the diameters and lengths of them as the sum of the diameters. ※In the case of multiple lesions fused and the boundary cannot be distinguished during the treatment, the diameter and length of the fused lesions are added together as the diameter sum. When the lesions are connected to each other, but the boundary of the lesions can still be identified, the diameter and length of each lesion are added as the diameter sum.

7. Criteria for determining the effect of non-target lesions ・CR (Complete Response): Complete remission All non-lymph node non-target lesions disappeared, and the short diameter of all lymph node non-target lesions did not reach 10 mm. ・Non-CR/non-PD: non-CR/non-PD There is one or more non-target lesions remaining (including the remaining non-target lesions of lymph nodes with a short diameter of more than 10 mm). ・PD (Progressive Disease): Disease progression "Significant deterioration" (including recurrence) of existing non-target lesions.

When there is a measurable lesion: Even if the effect of the target lesion is SD or PR, when "significant deterioration" is judged based on the change in the non-target lesion, the non-target lesion must be observed to have an overall increase in tumor volume sufficient to discontinue treatment markedly worsened. When the effect of the target lesion is SD or PR, the increase in the tumor volume of the non-target lesion to the extent that the reduction of the tumor volume can be greatly recovered is determined as "significant deterioration", otherwise, it is determined as Non-CR/non-PD. .

Only in the case of unmeasurable lesions: If the increase of the non-target lesion significantly exceeds the tumor volume equivalent to a 20% increase in diameter and length and a 73% increase in tumor volume as the standard, it is judged as "significant deterioration".

・NE (Not Evaluable): Unevaluable Cases that cannot be examined due to some reasons, or cases that cannot be judged as CR, Non-CR/non-PD, PD.

8. Whether new lesions appear When a lesion that did not exist at the baseline examination was confirmed after the start of treatment, it was determined that a "new lesion" appeared.

Among them, the determination of "new lesions" must not be due to changes in imaging methods or changes in imaging modality from the examination at the baseline assessment, or changes in images due to conditions other than tumors. Like the change above. For example, cystic lesions in the lesions caused by necrosis of liver metastases are not new lesions. At baseline (pre-enrollment assessment), the newly confirmed lesions in the sites that were not set as required by examination are new lesions.

When a lesion disappears and reappears, continue to measure. Among them, the effect at the time point when the lesions reappeared varies according to the status of other lesions. When lesions reappeared after CR, PD was determined at the time point of reappearance. On the other hand, in the case of PR or SD, when the temporarily disappeared lesion reappears, the effect is calculated by adding the diameter of the lesion to the sum of the diameter of the residual lesion. That is, in a state where multiple lesions remain, one lesion appears to "disappear" and then reappears, which alone cannot be judged as PD. PD is determined when the diameter of all the lesions and the criteria for PD are met. The reason for this is the perception that most lesions do not really "disappear", but are not visualized due to the limitation of the resolution of the diagnostic imaging tools used.

When there is a possibility of a new lesion but it cannot be determined, it will not be determined as a new lesion, and the image examination will be performed again at appropriate intervals in clinical practice. If it is determined to be a new lesion according to the image inspection performed again, the image inspection day at the time point of the new lesion is determined, and it is determined that a new lesion occurs.

New lesions were judged when FDG-PET positive lesions (FDG aggregation with an uptake of FDG that was 2 times greater than the surrounding tissue was observed in attenuation-corrected images) were found at sites that were negative for FDG-PET according to baseline. Baseline FDG-PET was not performed, and when FDG-PET-positive lesions were found by FDG-PET after the start of treatment, the FDG-PET-positive site was confirmed by CT or MRI to be absent at baseline. When lesions were observed, new lesions were determined.

9. Overall Response The overall response (Overall response) is based on the combination of the effect of target lesions, the effect of non-target lesions, and the presence or absence of new lesions, and is determined according to Table a below. The overall efficacy in the absence of non-target lesions at baseline was determined by the effect of target lesions and the appearance of new lesions, and the overall efficacy in the absence of target lesions at baseline was determined by the effect of non-target lesions And new lesions appear, according to Table b to determine.

[Table 4a] Table a Overall efficacy at each time point: in the presence of target lesions target lesion non-target lesions new lesions total efficacy CR CR none CR CR Non-CR / non-PD none PR CR No assessment none PR PR Non-PD or incomplete assessment none PR SD Non-PD or incomplete assessment none SD Incomplete assessment Non-PD none NE PD Do not ask with or without PD Do not ask PD with or without PD Do not ask Do not ask Have PD

[Table 4b] Table b Overall efficacy at each time point: only in the presence of non-target lesions non-target lesions new lesions total efficacy CR none PR Non - CR / non-PD none Non - CR / non-PD Incomplete assessment none NE Significant deterioration with or without PD Do not ask Have PD

10. Best Overall Response The overall response (overall response) was evaluated in the order of CR > PR > SD > PD > NE. Based on the overall response during the entire clinical trial period, the Best Overall Response was determined according to the following criteria (Table 1). c). When the definitions of multiple intervals are met, they are classified into better intervals in the order of CR>PR>SD>PD>NE.

・CR (Complete Response): Complete remission The case of obtaining 2 or more consecutive total curative effect CRs with an interval of more than 4 weeks (28 days). The day on which the CR was confirmed for the second time and the best overall CR was determined was the "CR Confirmation Day". ・PR (Partial Response): Partial mitigation Obtain the total efficacy (CR or PR) of more than 2 consecutive PRs with an interval of more than 4 weeks (28 days). The day on which the total effect of PR or above is confirmed for the second time and the best total effect PR is determined is the "PR confirmation day". ・SD (Stable Disease): Stable The best overall curative effect of CR or PR was not obtained, but no PD occurred in the overall curative effect determined within 6 weeks after the start of treatment, and the overall curative effect was more than SD for more than 1 time. ・PD (Progressive Disease): Progress The best overall curative effect does not meet any one of CR, PR, SD, and the overall curative effect is PD. ・NE (Not Evaluable): Unevaluable The overall efficacy is the case of NE.

[Table 4c] Table c Best overall efficacy initial overall efficacy The total effect of the next time The total effect of the next time best overall efficacy Either PR or CR SD PD SD Either PR or CR SD NE SD Either PR or CR PD - PD Either PR or CR NE NE NE Either PR or CR NE SD SD SD PD - PD SD SD PD SD SD NE PD PD NE NE PD PD NE NE NE NE NE NE PD PD [Example 1]

Example 1 The clinical therapeutic effect of tocilizumab (TCZ) + gemcitabine + nab-paclitaxel (N) in the unresponsive case of gemcitabine (G) + nab-paclitaxel (N)

Summary of the clinical trial In order to investigate the therapeutic effect based on the principle of inhibiting desmoplasia by blocking interleukin 6 (IL-6) signaling in the tumor microenvironment of pancreatic cancer, the inability to respond to GN For patients with resected and recurrent pancreatic cancer, 10 patients were administered a single dose of the anti-IL-6R antibody tocilizumab (TCZ), which is an IL-6 signaling inhibitor, and the GN therapy "targeting gemcitabine and Phase I clinical trial of tocilizumab plus gemcitabine-nab-paclitaxel combination therapy for metastatic pancreatic cancer unresponsive to nab-paclitaxel (EPOC1804)="A Phase I study of tocilizumab plus gemcitabine/nab-paclitaxel in patient with gemcitabine/nab-paclitaxel-refractory metastatic pancreatic cancer (EPOC1804)”. Since there is no case of co-administration of TCZ and GN therapy in humans so far, the purpose is to study the safety and tolerability of TCZ+GN. The purpose of concomitant use of TCZ is to relieve GEM resistance. Therefore, the subject is set to obtain a partial response (PR) or higher or equivalent to PR based on RECIST criteria ver. 1.1 by GN therapy for unresectable and recurrent pancreatic cancer Pancreatic cancer patients with liver metastases who became unresponsive after antitumor effects.

Dose and Administration TCZ: The results of the GEM+TCZ trial (Mitsunaga S. et al., J Med Diagn Meth 6(1): 234, 2017) showed that TCZ administration was tolerated at 8 mg/kg. In this clinical trial, GN therapy and TCZ were used together. GN therapy frequently caused more severe neutropenia than GEM single-dose, and TCZ-induced neutropenia was expected. Therefore, considering the safety The dose level of TCZ was halved, also set at 4 mg/kg. In a previously conducted Phase II clinical trial for Castleman's disease, TCZ was administered at 2 mg/kg, 4 mg/kg, and 8 mg/kg every 2 weeks (7 cases), and 1 case was administered at 2 mg/kg. Discontinued due to anti-IL-6R antibody performance. In addition, when a low dose of TCZ is administered, TCZ easily disappears from the blood when there is a large amount of IL-6 in the blood that is not bound to the IL-6 receptor, so there is an IL-6 signaling system. There is a risk of triggering a large amount of inflammatory response with abrupt movements. Therefore, it is suggested that at low doses of TCZ, especially 2 mg/kg, sufficient IL-6 inhibitory effect may not be obtained due to the expression of anti-TCZ antibodies or the disappearance of TCZ in the early stage. To sum up, in this clinical trial, the initial dose of TCZ was set to 8 mg/kg, which was the same as that of the GEM+TCZ trial, and the dose level was halved to 4 mg/kg as an evaluable setting, and 2 mg/kg was not evaluated. . Taking 28 days as a cycle, Day 1 of the first cycle is the day of TCZ injection, and Day 1 of the additional cycle is the day of the first injection of TCZ+GEM or TCZ+GN in each cycle.

Concomitant medication (Gem+Nab-PTX): In the MPACT trial, a large-scale phase III comparative trial targeting distant metastatic pancreatic cancer, GEM was administered on Day 1, Day 8, and Day 15 with a cycle of 28 days 1000 mg/m ² + nab-PTX 125 mg/m ² . As a result, the relative dose intensity of GEM was 75% and that of nab-PTX was 80% (Von Hoff DD. et al., N Engl J Med. 2013 Oct 31; 369(18): 1691-703). In the phase I trial of ruxolitinib, which inhibits the intracellular signaling of IL-6, and GN, the recommended doses of GN administered in the same way are GEM: 750 mg/m ² , nab-PTX: 100 mg/ m ² (Bauer TM. et al., Onco Targets Ther. 2018 Apr 30; 11: 2399-2407). In summary, when TCZ is used in GN, a cycle of 28 days is used to administer a more standard dose on Day 2, Day 9, and Day 16 (Day 1, Day 8, and Day 15 in the additional cycle). Reduced GEM 750 mg/m ² + nab-PTX 100 mg/m ² .

In the GEM+ TCZ trial (Mitsunaga S. et al., J Med Diagn Meth 6(1): 234, 2017), the PFS in the CRP 2-10 mg/dL population was 3.6 months (95% confidence interval: 1.0- 4.4), so it is considered that TCZ+GN is expected to be continuously invested for more than 1 month. However, considering the fragility of pancreatic cancer patients after the second treatment and the risk of severe infection caused by CRP inhibition or heat dissipation caused by TCZ, the administration period of this clinical trial was set to be 28% of TCZ+GN for one cycle. sky. As the implementation standard of the additional cycle, only patients who do not meet the treatment discontinuation standard and clinical trial discontinuation standard and meet all the following standards at the end of the first cycle, the additional cycle of TCZ (8 mg/kg) + GN administration will be administered . In cases where GEM or GN cannot be administered during the additional cycle, TCZ will not be administered separately.

When the anti-tumor effect based on the RECIST criteria ver.1.1 is above or equivalent to PR (the tumor shrinks by more than 20% or the tumor marker is reduced by more than 50%), or the disease is controlled, the investigator judges that the treatment plan should continue. have clinical significance.

Clinical trial design In order to ensure the safety of the subjects, the 3+3 design commonly used in phase I trials of anticancer agents is adopted. Figure 1 shows an outline of the clinical trial design.

<Dose finding cohort> To determine the recommended dose of TCZ, 1 cycle of TCZ 8 mg/kg + GN concomitant therapy was performed, and tolerance was assessed according to the frequency of DLT. When TCZ 8 mg/kg could not be tolerated, 1 cycle of TCZ 4 mg/kg + GN combined therapy was performed, and the tolerance was evaluated according to the frequency of DLT. Up to 12 subjects for DLT assessment.

<Expansion cohort> When the recommended dose of TCZ determined by the dose-discovery cohort and the enrollment of the dose-discovery cohort is less than 10, exploratory assessment of the efficacy of the recommended dose of TCZ determined by the dose-discovery cohort when used in combination with GN sex and safety.

The incidence of adverse events and the incidence of dose-limiting toxicity (DLT) as the main evaluation items, the remission rate (Response rate: RR) and disease control rate determined by the investigator as the main secondary evaluation items. (Disease control rate: DCR) for evaluation. The dose-limiting toxicity (DLT) evaluation period was 28 days after the start of administration.

Evaluation and monitoring During the entire clinical trial period, all patients were carefully monitored for adverse events, according to the "Common Terminology Criteria for Adverse Events (CTCAE) v4.0-JCOG) [corresponding to the "Common Terminology Criteria for Adverse Events (CTCAE) v4.0-JCOG) In CTCAE v4.03/MedDRA v12.0]", the event name and grade of adverse events were classified. Patients underwent tumor assessment at enrollment (before administration) and on Day 28 of Cycle 1. Patients who subsequently underwent a booster cycle underwent tumor assessment on day 22 of that cycle. Responses were assessed by investigators using the "New Response Evaluation Criteria in Solid Cancers (RECIST Criteria) Revised 1.1-Japanese JCOG version-: Revised RECIST guideline (version 1.1)" for tumor shrinkage effect.

Regarding dose-limiting toxicity (DLT), the evaluation period was set to be 28 days from the start date of TCZ administration. Again. If the adverse events that continue to occur after the 28th day are events related to the DLT determination, the DLT evaluation period will be extended. It is up to the investigator to determine whether it is a DLT. Among them, the case where the causal relationship with TCZ+GN combined therapy can be denied is determined as not belonging to DLT. Also, in the event of DLT occurring but not meeting the protocol treatment discontinuation criteria, the treatment regimen was continued. Select the subjects who were administered TCZ on Day 1 and GN on Day 2, and who obtained sufficient data for DLT assessment as the subjects of DLT assessment. Among them, the case where DLT occurred even when GN was not administered was set as the evaluation object.

<DLT standard> (1) Decreased neutrophils in Grade 4 (<500/mm ³ ) for more than 7 days (2) Grade 3 (<1,000/ mm ³ ) or more neutropenia (3) Grade 4 (<25,000/mm ³ ) thrombocytopenia that persisted for more than 7 days (4) Blood transfusion due to Grade 3 or more thrombocytopenia (5) ) AST/ALT elevation of Grade 4 or AST/ALT elevation of Grade 3 that persists for more than 7 days (6) Non-hematological toxicity of Grade 3 or higher (among which, digestive system symptoms of Grade 3 that can be controlled by supportive therapy, Electrolyte abnormalities above Grade 3 and abnormal test values, controllable Grade 3 high blood pressure, and Grade 3 infusion reactions are excluded)

As the benchmark for the patient population of this clinical trial, the C-reactive protein (CRP) in blood, which suggests that it is more resistant to the participation of IL-6 produced by tumor cells, stromal cells, and immunocompetent cells in pancreatic cancer tissue, is set at 0.5 Patients with advanced pancreatic cancer with unresponsive GN above mg/dL and below 10.0 mg/dL were selected as the inclusion criteria.

Subjects who meet all of the following selection criteria and do not meet any exclusion criteria are eligible. <Criteria for selection> (1) The age at the time of obtaining consent is 20 years or older. (2) The pathological diagnosis shows invasive pancreatic ductal carcinoma, adenocarcinoma, adenosquamous epithelial carcinoma, or cancer and the clinical diagnosis is not inconsistent with metastatic pancreatic cancer.

(3) GN therapy for unresectable and recurrent pancreatic cancer to obtain partial response (PR) or higher based on Response Evaluation Criteria for Solid Tumors (RECIST) ver.1.1 or equivalent to PR (based on RECIST ver1.1 The tumor length and diameter in the lesions can be measured and the anti-tumor effect of tumor marker CA19-9 reduced by more than 20%, or the blood concentration of tumor marker CA19-9 is reduced by more than 50%) and becomes unresponsive.

(4) It is judged that GEM 750 mg/m ² + nab-PTX 100 mg/m ² can be administered safely to unresectable and recurrent pancreatic cancer. (5) There is liver metastases based on the target lesions of RECIST criteria ver 1.1, and liver biopsy can be performed. Also, agree to provide the collected tumor tissue and blood samples.

(6) Contrast CT examination or contrast MRI examination can be performed. (7) ECOG daily performance status (PS) is 0-1. (8) Maintain adequate organ function meeting the following conditions within 7 days before enrollment. Furthermore, when there are multiple check values, the check value closest to the date of enrollment is used.・Neutrophil count 1,500/ ^mm3 or more ・Platelet count 100,000/ ^mm3 or more ・Hemoglobin 8.5 g/dL or more ・Serum creatinine less than 1.2 mg/dL ・Serum total bilirubin less than 2.0 mg/dL ・AST, ALT Below 120 U/L

(9) CRP is 0.5 mg/dL or more and 10.0 mg/dL or less. (10) Peripheral sensory neuropathy is below Grade 2. (11) At least expected to survive for more than 2 months. (12) Be fully informed of the content of this clinical trial, with the written consent of the patient.

<Exclusion criteria> (1) There is obvious body cavity effusion and edema. (2) Brain metastases with symptoms are present. (3) Patients with active repeat cancer (a disease-free period of more than 3 years is allowed. In addition, active repeat cancer does not include cases where intraepithelial cancer and intramucosal cancer are judged to be cured by local treatment) .

(4) There was a history of cholangiojejunostomy in the past. (5) Received blood transfusion within 4 weeks before entering the group. (6) As of the enrollment time point, the last surgery (except percutaneous transhepatic biliary drainage or endoscopic biliary drainage) has not reached 4 weeks.

(7) Surgery is scheduled to be performed during the clinical trial. (8) There is a history of administration of IL-6 signaling inhibitors (JAK inhibitors, etc.) in the past. (9) There is a history of administration of immunotherapy (cancer vaccine, immune checkpoint inhibitor, etc.) in the past.

(10) Administered biological agents (TCZ, trastuzumab, infliximab, etanercept, adalimumab, etc.) within 4 weeks before enrollment. (11) Administered other clinical trial drugs within 4 weeks before enrollment. (12) Concurrent infectious diseases requiring systemic administration of antibiotics, antiviral drugs, and antifungal drugs.

(13) Positive for HCV antibody, positive for HBs antigen antibody, positive for HBs antibody or positive for HBc antibody, or positive for HBV-DNA quantitative test when both are positive, or positive for HIV antibody. (14) Suffering from non-neoplastic diseases (allergic diseases, asthma, etc.) requiring systemic administration of adrenocortical hormones. (15) Complicated with idiopathic pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-induced pneumonia and other lung injury and tuberculosis, or have related past medical history.

(16) Patients with clinically problematic heart disease (uncontrollable hypertension, unstable angina pectoris, stagnant heart failure, severe arrhythmia requiring drug treatment, myocardial infarction within 12 months before enrollment, etc.). (17) Suffering from a mental illness that is judged by the researcher or assistant researcher to hinder the understanding of consent or clinical trial implementation.

(18) Suffering from poorly controlled diabetes mellitus (standard HbA1c value is 7.5%, clinical judgment is preferred). (19) There is a history of severe allergy to levofloxacin and other drugs in the past.

(20) Patients with the following diseases, which the researcher or assistant researcher judges not suitable for participating in clinical trials based on medical basis. Circulatory organ diseases, blood/hematopoietic organ diseases, respiratory system diseases, neuromuscular diseases, endocrine diseases, urinary system diseases, digestive system diseases, macular edema, myelofibrosis, polycythemia vera, rheumatoid arthritis and other systemic diseases Inflammatory disease.

(21) For women who may be pregnant, the pregnancy test results within 7 days of enrollment (serum test when the results of urine test are in doubt) are not negative. (22) Inability to agree to adequate contraception for at least 1 month after the last dose from the time of consent. Also, for women, it is not acceptable to abstain from breastfeeding for at least 1 month from the time of consent to the last dose. (23) Other investigators or assistant investigators judge that they are not suitable to participate in this clinical trial.

Results The results of this clinical trial are shown in Table 1. The primary assessment was the incidence of dose-limiting toxicity, which was not confirmed. As the remission rate of the sub-assessment item, the evaluation results were 1 PR (partial response: partial remission), 6 SD (stable disease: stable), and 3 PD (progressive disease: progressive). According to a pilot study, the response rate (RR) of GN therapy for pancreatic cancer patients who did not respond to chemotherapeutic agents was 0% (Nishioka et al., Cancer Therapy Society 2019), 3.2% (Yang et al. J Formos Med Assoc 2020 Jan; 119 (1 Pt 1): 97-105), the RR of GN therapy combined with anti-IL-6R antibody was 10%. Among the above-mentioned 6 patients with SD (stable), 3 patients observed a reduction of the tumor marker CA19-9 by more than 30%, and maintained SD for a long time, and 1 patient had a partial response, which showed that it was equivalent to a partial response (PR). A total of 4 patients (40%) had the effect. In a pilot study, the disease control rate (DCR) of GN therapy for pancreatic cancer patients who did not respond to chemotherapeutic agents was 33% (Nishioka et al., Cancer Therapy Society 2019), 19.4% (Yang et al. J Formos Med Assoc. 2020 Jan; 119 (1 Pt 1): 97-105), the DCR of the anti-IL-6R antibody + GN combination therapy was 70%. Regarding the therapeutic effect on the pancreatic cancer group ineffective in standard treatment, it was confirmed that both the partial remission rate and the disease control rate can be regarded as a good anti-tumor effect.

It can be confirmed that these unexpected and excellent combined effects are due to the improvement of drug penetration due to the improvement effect of the microenvironment including tumor stroma found in Examples 2 and 3 described later. The excellent antitumor effect of non-responders was closely related to the inhibition of the tumor marker CA19-9 (Fig. 2).

[Table 5] Table 1 Results of clinical trials age gender CRP Baseline CA19-9 TCZ＋GN Cycle(s) CA19-9_ Best change from baseline RECIST_ Best Overall Response GAP001 66 F 4.1 50077 6 -80% SD GAP002 66 F 0.3 1344 1 No tendency to decrease PD GAP003 62 M 20.1 729 1 No tendency to decrease PD GAP004 76 M 17.8 37005 3 -55% SD GAP005 50 M 2.8 15065 1 No tendency to decrease SD GAP006 49 F 2.9 241 1 -twenty three% SD GAP007 74 F 2.3 18547 1 -5% PD GAP008 68 M 2.4 2188 2 -twenty four% PR-in GAP009 48 M 3.7 220 4 -48% SD GAP010 75 M 9.2 25.1 1 -15% SD [Example 2]

Example 2 Clinically, anti-IL-6R antibody inhibits connective tissue hyperplasia The fibrotic-rich tumor stroma is called connective tissue hyperplasia, which is a feature of pancreatic cancer and is considered to be one of the reasons for non-response to chemotherapy. The reason for the proliferation of connective tissue in pancreatic cancer is considered to be as follows. Activated fibroblasts expressing α-smooth muscle actin (α-SMA) are vigorously grown due to growth factors, cytokines, etc. produced from pancreatic cancer cells. Extracellular matrix such as collagen or fibronectin. In EPOC1804, tumor tissue samples of pancreatic cancer liver metastases before and after GN+TCZ administration were collected, and the relationship between the inhibition of IL-6 inhibition-induced connective tissue hyperplasia formation and the antitumor effect was studied.

After obtaining the consent of the patients who participated in the phase I clinical trial (EPOC1804) of single administration of the anti-IL-6R antibody tocilizumab (TCZ) in combination with GN therapy described in Example 1, GN+TCZ was collected using an 18-gauge needle. Before administration (Day 0) and after administration (Day 28), tumor tissues of pancreatic cancer liver metastases of patients were immediately fixed with 10% neutral formalin. The fixed tumor specimens were dehydrated within 48 hours and embedded in paraffin to prepare tumor specimen blocks (FFPE blocks). A thin section of tumor tissue with a thickness of 4 μm was cut from the FFPE block using a microtome, and attached to a glass slide to prepare a tumor section specimen. The tumor sections were subjected to hematoxylin-eosin (HE) staining and immunohistochemical staining (Immunohistochemistry; IHC) with anti-α-SMA antibody and anti-phospho-STAT3 antibody as primary antibodies.

The results are shown in FIG. 3 . According to the analysis of the samples from the subjects with good therapeutic effect (GAP01), compared with before the administration of GN+TCZ, the HE-stained tissue images after the administration of GN+TCZ showed that the fibrous interstitial tissue of the tumor was significantly destroyed. It was confirmed by IHC method that the positive area ratio of fibrosis marker α-SMA in tumor tissue was 19% before administration (pre), but it became 7% after administration (post), which was higher than that after administration. An unexpectedly significant reduction was observed before, which was 63%, confirming the inhibitory effect of tumor stroma on connective tissue proliferation after GN+TCZ administration. Regarding this connective tissue proliferation inhibitory effect, the phosphorylation of IL-6 signaling downstream factor STAT3 (phosho-STAT3) (0.9%) after GN+TCZ administration was reduced by 83% compared to before administration (5%), due to the lack of response to GN. The phosphorylation of STAT3 (phosho-STAT3), a downstream factor of IL-6 signaling, was significantly inhibited by administration of TCZ+GN to the patient, so it was confirmed that TCZ was effective. From the above, it was confirmed that TCZ+GN therapy induces excellent inhibition of connective tissue proliferation in pancreatic cancer, and exerts the antitumor effect shown in Example 1. [Example 3]

Example 3 Clinical evaluation of low molecular weight infiltration under the action of TCZ (levofloxacin infiltration under the action of TCZ) Evaluation of tumor tissue samples of pancreatic cancer liver metastases from patients before and after administration of TCZ+GN, by using stroma Mass spectrometry imaging (MALDI-MSI) of matrix assisted laser desorption/ionization (MALDI) to evaluate the hyperpenetration of low molecular weight drugs into tumors mediated by IL-6R inhibition, research and anti-tumor effects relationship.

In the "Phase I clinical trial of tocilizumab and gemcitabine-nab-paclitaxel combination therapy for metastatic pancreatic cancer unresponsive to gemcitabine and nab-paclitaxel" described in Example 1 (EPOC1804), a patient After informed consent was obtained, before the administration of GN+TCZ on day 0 (before administration) and after administration of the drug on day 28 (after administration), an 18-gauge needle was used to collect the thickness of pancreatic cancer tissue from the patient's liver metastases. Core needle biopsy samples. Before biopsy, the low molecular weight antibiotic levofloxacin was pre-administered to the patient. The collected biopsy samples were immediately frozen at about -20°C. Samples were stored at -80°C before use. Using a cryostat, 3 serial sections were obtained from each sample and mounted on indium tin oxide coated glass slides. The tissue sections were sprayed with matrix (α-cyano-4-hydroxycinnamic acid; αCHCA) and isotope-labeled levofloxacin as an internal standard using a TM Sprayer (HTX Imaging). Mass spectra and positional information were obtained using Solarix (MALDI-FTICR) (Bruker Daltonics). After MALD-MSI analysis, the matrix was removed, and the samples were stained with hematoxylin and eosin to evaluate the tissue structure and distribution of levofloxacin. Finally, the MALDI-MSI data were parsed using Multimaging software (ImaBiotech), and the distribution of levofloxacin was depicted using a heat map. Images were normalized based on the intensity of the internal standard.

The results are shown in FIG. 4 . The concentration of levofloxacin in the tumor tissue before the administration was 10.4 μg in the tumor specimen collected from the pancreatic cancer liver metastases of the patient of the TCZ+GN administration effective case (patient ID GAP001) found in Example 1 On the other hand, the levofloxacin concentration after administration was 17.1 μg/g, and the increase rate of levofloxacin concentration in tumors after GN+TCZ administration was 64.4% compared with that before administration. Compared with the accumulation of levofloxacin in the tumor area of the sample before administration, the post-administration sample collected from the same target lesion area of pancreatic cancer liver metastases in the same patient showed that levofloxacin accumulated in the tumor. In conclusion, it was confirmed by the MALDI-MSI method that the improvement effect of the microenvironment including the tumor stroma as found in Example 2 increased the penetration of the low molecular weight chemotherapeutic agent levofloxacin into the tumor. The reason is believed to be that, compared with GN therapy, TCZ+GN therapy induces low molecular weight drugs such as gemcitabine or albumin-bound paclitaxel, and high molecular weight antibody drugs or as shown in Example 4 by remodeling the tumor microenvironment. It shows the infiltration of immune cells into the tumor. These results corroborate the antitumor effect found in Example 1. [Example 4]

Example 4 Dosage of TCZ based on the simulation of GN+TCZ In order to select the optimal dose of TCZ in the combination regimen of TCZ+GN+atezolizumab (ATZ, anti-PD-L1 antibody preparation) for pancreatic cancer, semi-mechanical pharmacokinetics were used (PK)-Pharmacodynamic (PD) model to study the effect of G, N and TCZ on neutrophil number. The neutrophil life cycle model was reported by Friberg et al. (J Clin Oncol. 2002 Dec15; 20(24): 4713-21). Lines G and N were used as models to inhibit the growth of neutrophils. On the other hand, TCZ has been reported to decrease circulating neutrophils (Chen et al. J Clin Pharmacol. 2014 Oct; 54(10): 1097-107., Laurence et al. Eur J Clin Invest. 2017 Oct; 47(10): 736-745.), which was modeled as one that increases neutrophil clearance from circulating blood. The model parameters of G, N and TCZ in each process are based on literature (Daniel et al. N Engl J Med. 2013; 369: 1691-703, Chen et al. J Clin Pharmacol. 2014 Oct; 54(10): 1097-107., Gibiansky et al. J Pharmacokinet Pharmacidyn. 2012 Feb; 39(1): 5-16.). The structure of this semi-mechanical PK-PD model is shown in FIG. 5 .

In order to confirm whether this model accurately describes the change in neutrophil number, "Tocilizumab for metastatic pancreatic cancer unresponsive to gemcitabine and nab-paclitaxel" described in Example 1 was used in combination with gemcitabine-nab-paclitaxel The actual observed and predicted neutrophil counts in the Phase I clinical trial of the therapy (EPOC1804) are shown in Figure 6. There were large differences in observed neutrophil numbers, but the predictions showed a good trend towards the overall observations.

Second, to determine the dose of TCZ in pancreatic cancer, for 4 different doses: once 4 mg/kg biweekly (q2w), once 8 mg/kg biweekly (q2w), once 4 mg/kg kg once every four weeks (q4w) and 8 mg/kg once every four weeks (q4w), to predict the evolution of neutrophil numbers in the case of combined use of TCZ+GN. By using the model described above, it was simulated whether the reduction in neutrophil number meets the GN reduction benchmark described in the accompanying instructions for Abraxane for pancreatic cancer. As a result, 7 days after the start of administration, the TCZ doses of 4 mg/kg q2w, 8 mg/kg q2w, 4 mg/kg q4w and 8 mg/kg q4w were 26%, 27%, 23% and 23%, respectively. Twenty-seven percent of patients were below the dose reduction baseline (less than 1000 cells/mm ³ ) (Figure 7 and Table 2). Likewise, on day 14, 18%, 21%, 18% and 22% of patients did not meet the dose-reduction baseline for neutrophil counts, respectively. In addition, on the 28th day of administration, 9%, 8%, 10%, and 7% of patients did not recover to the criteria for delaying administration (less than 1500 cells/mm ³ ).

Based on the results of the simulation, the ratio of patients requiring a dose change/dosing delay was at all time points studied (Days 7, 14 and 28), at the various TCZ doses studied (4 mg/kg q2w, 8 mg/kg No clinically meaningful differences were shown between q2w, 4 mg/kg q4w, and 8 mg/kg q4w).

Considering that the TCZ dose of 8 mg/kg Q4W once showed efficacy on pancreatic cancer (refer to Example 1), it is expected that 8 mg/kg Q2W once (approved dose) will also be effective. In the TCZ+GN+ATZ combination regimen for pancreatic cancer, from the point of view of safety, based on the insights of the neutrophil numbers predicted by simulation, we concluded that the doses of TCZ under study (4 mg/kg Q2W once a time) can be used. , 8 mg/kg Q2W once, 4 mg/kg Q4W once, and 8 mg/kg Q4W once) were used together. [Table 6] Table 2 Percentage of patients requiring dose change/dosing delay (%) Day7 Day14 Day28 Neutrophil number <1500 (cells/mm ³ ) Neutrophil number <1000 (cells/mm ³ ) Neutrophil number <500 (cells/mm ³ ) Neutrophil number <1000 (cells/mm ³ ) Neutrophil number <500 (cells/mm ³ ) Gem＋nabPac 16 6 27 9 11 TCZ q2w_4 mg 26 8 18 6 9 TCZ q2w_8 mg 27 8 twenty one 7 8 TCZ q4w_4 mg twenty three 7 18 6 10 TCZ q4w_8 mg 27 8 twenty two 8 7 Refer to the instructions in the prepackage to make necessary adjustments to Gem+Nab-PTX Reduced dose - Nab-PTX at 25 mg/m ² - Gem at 200 mg/m ² Suspension of Day8 investment Dose reduction (personalized) Suspend day15 investment Next dosing cycle postponed [Example 5]

Example 5 CD45-positive cells (neutrophils, neutrophils, Confirmation of infiltration of immune cells such as lymphocytes, monocytes), CD3 positive cells (T cells), CD8 positive cells (cytotoxic T cells, some NK cells) and dendritic cells into tumors.

The infiltration of a variety of immune cells can be detected in the tumor microenvironment surrounding the tumor tissue. In recent years, it has been gradually discovered that these immune cells are not harmless bystanders, but are carcinogenic-related factors that cause pancreatic cancer. Therefore, by administering anti-IL-6R antibody, anti-PD-L1 antibody and gemcitabine to KPΔC mice, the gene profiling of tumor-infiltrating lymphocytes (TIL) was analyzed, and the role of IL-6 in immunosuppression was determined. Detailed roles in the tumor microenvironment. For this purpose, transgenic KPΔC mice with natural onset of pancreatic cancer and 3 mouse systems with the genetic background shown below (LSL-Kras ^G12D (Kras ^tm1Tyj ) (Hingorani et al., 2003; Cancer Cell 4, 437 -450), Ptf1a-cre ^ex1 ( ^{Ptf1a tm1(cre)Hnak} ) (Nakhai et al., 2007; Development 134, 1151-1160), Trp53 flox ^/ flox (Trp53 ^tm1Brn ) (Marino et al., 2000; Genes Dev 14, 994-1004)) mice were mated, and LSL-Kras ^G12D , Ptf1a-cre ^ex1 , Trp53 flox ^/ flox were produced, and experiments were carried out.

Mice were bred under specific pathogen-free conditions for all experiments. After KPΔC mice reached 4 to 5 weeks of age, the mice were divided into 5 groups, and the mice were treated with mouse IgG1 isotype control antibody, anti-mouse PD-L1 (B7-H1) antibody (purchased from BioXCell), anti-mouse antibody alone or in combination. IL-6R antibody (MR16-1) (provided by Zhongwai Pharmaceutical) and gemcitabine (provided by the Hospital Pharmacy of Klinikum Rechts der Isar (Affiliated Hospital of Technical University of Munich)) were administered to the mice.

The combination of administration was as follows: group 1 (control administration group) was administered with isotype control IgG antibody, group 2 (IL-6R antibody administration group) was administered with anti-IL-6R antibody, and group 3 (PD-L1 antibody administration group) was administered with anti-IL-6R antibody. group) anti-PD-L1 antibody, group 4 (IL-6R antibody + PD-L1 antibody combined administration group) combined with anti-IL-6R antibody and anti-PD-L1 antibody, and group 5 (IL-6R antibody +PD-L1 antibody + gemcitabine concomitant administration group) and administered three doses of anti-IL-6R antibody, anti-PD-L1 antibody and gemcitabine in combination.

The various agents were administered via intraperitoneal injection. When administered to mice, InVivoPlus mouse IgG1 isotype control, InVivoMAb anti-mouse PD-L1 antibody (B7-H1), and anti-mouse IL-6R antibody (MR16-1) were prepared in InVivoPure pH 6.5 dilution buffer. dilution. KPΔC mice aged 4 to 5 weeks were administered four times (days 0, 1, 7 and 14) an isotype control antibody or an anti-IL-6R antibody (MR16-1) at a dose of 30 μg/kg. Anti-PD-L1 antibody (25 μg/kg) or gemcitabine (100 mg/kg) was administered 5 times (days 0, 3, 7, 10 and 14). After the administration, the animals were euthanized, and cells were collected from pancreatic cancer tissue and spleen, and further analysis was performed by the method described below.

Cells were isolated from pancreatic cancer tissue and spleen to prepare a single-celled cell suspension (single cell suspension), and the phenotypic analysis of the immune cells contained in each was assessed by fluorescence-activated cell sorting (FACS). Fresh pancreas and spleen were collected from KPΔC mice after administration, and single-cell suspensions of each tissue were prepared.

The method is disclosed below. The harvested pancreas was immediately minced and incubated with PBS containing 1.2 mg/ml collagenase type IV (Sigma Aldrich) and 0.1 mg/ml soybean trypsin inhibitor (Sigma Aldrich) at 37°C for 10 minutes, followed by incubation. The cell suspension was prepared by passing it through a 70 μm cell strainer. The harvested spleen was immediately crushed and passed through a 70 μm cell strainer to prepare a cell suspension. Each cell suspension was washed once with PBS/1% FCS and treated with erythrocyte lysis buffer (Sigma Aldrich) for 90 seconds to remove erythrocytes. After washing the cell suspension again, using Fc-block (CD16/32 Fc-block eBiosciences) prepared by diluting Fc receptors in PBS containing 1% FCS, and incubating at 4°C for 20 minutes. Treatment to block non-specific binding of the FC region of monoclonal antibodies. Thereafter, the cell suspension was washed with a centrifuge, and the cell surface markers were stained with the following antibodies diluted in PBS containing 1% FCS for 30 minutes, protected from light, at 4°C: CD19 (colonized eBio1D3). , eBioscience), F4/80 (selection BM8, eBioscience), CD11b (selection M1/70, eBioscience), CD45 (selection 30-F11, Bioscience), CD3e (selection 145-2C11, eBioscience), CD4 ( GK1.5, BioLegend), CD8 (53-6.7, BioLegend), CD11c (N418, BioLegend), CD206 (C068C2, BioLegend), Gr-1 (RB6-8C5, BioLegend) . Fluorescence compensation was performed using single-stained samples with each antibody, and no-stained controls were used to exclude false positive signals. Flow cytometry was performed using a Gallios flow cytometer (Beckman Coulter) after assessing viability by propidium iodide (PI, Sigma Aldrich) staining prior to flow cytometry and gating to exclude dead cells. Data analysis was performed using the FlowJo software suite.

The percentage of cells reported in each graph refers to the ratio of cells positive for cell surface markers relative to the total number of viable cells obtained from a particular mouse specimen. Data are presented as mean ± standard deviation. For comparison between groups, a two-sided Student's t-test was performed. Statistical significance was set as *P<0.05, **P<0.01, ***P<0.001. Statistical analysis was performed using GraphPad PRISM (registered trademark) 8.0 software.

The combinations of markers used to identify various immune cells used in flow cytometry are summarized in Table 3 below. As shown in Fig. 8, by the administration of the IL-6R antibody administration group (73.3%) or the IL-6R antibody + PD-L1 antibody combined administration group (87.1%), compared with the control administration group (40.8%) ), the CD45-positive lymphocytes (including neutrophils and monocytes) infiltrating into pancreatic cancer tumor tissue showed a statistically significant hyperinfiltration state. In addition, according to the detailed analysis of the immune response in the pancreatic cancer tumor tissue microenvironment, it was shown that the IL-6R antibody + PD-L1 antibody in the combined administration group was killed by CD3 positive T cells and CD8 positive cells compared with the control administration group. The infiltration of immune cells such as sex T cells (CTL), dendritic cells (DC) and B cells was statistically significant (Table 4). The ratios of increase in the combined IL-6R antibody + PD-L1 antibody administration group compared with the control administration group were CD3 positive T cells: 161.4%, CD8 positive CTL: 529.2%, DC: 152.9%, B cells: 68.9%. Furthermore, by using the chemotherapeutic agent gemcitabine in combination with anti-IL-6R antibody and anti-PD-L1 antibody, there was a statistically significant increase in infiltrating B cells compared to the control group, with a ratio of 487.2%. It can be seen that by co-administration of IL-6R antibody + PD-L1 antibody + gemcitabine, compared with the control group, not only B cells, but also other assessed immune cells infiltrated into the tumor, and the ratios were CD45 positive. Lymphocytes: 33.4%, CD3-positive and CD45-positive T cells: 69.5%, CD8-positive and CD45-positive CTLs: 406.5%, and DCs: 250.5%. The confirmation of marked hyperinfiltration of B cells generated by administration of IL-6R antibody + PD-L1 antibody + gemcitabine strongly suggests the induction of acquired immunity.

Antigen-presenting cells such as dendritic cells of the acquired immune system activate T cells or B cells by recognizing specific antigens and activate the immune response of living organisms. In this study, it was confirmed for the first time that by administering IL-6R antibody + PD-L1 antibody + gemcitabine to pancreatic cancer tumor tissue, the infiltration of CD45-positive immune cells represented by DC, T cells, and B cells into the tumor was increased. , this is an important and epoch-making discovery that proves that dendritic cells activate T cells or B cells by recognizing specific cancer antigens, and as a result, the anti-tumor effect shown in Example 6-2 is induced after the induction of innate immunity.

Based on these results, it was confirmed that the infiltration of major immune cells including T cells, neutrophils or monocytes into pancreatic cancer tumor tissue by the combined use of anti-IL-6R antibody + anti-PD-L1 antibody been significantly promoted. The addition of standard treatment gemcitabine on the basis of concomitant use of anti-IL-6R antibody + anti-PD-L1 antibody not only maintained the infiltration of various immune cells in pancreatic cancer tumor tissue, but also confirmed that the activation of T cells and B cells And the evidence of inducing acquired immunity has successfully obtained epoch-making insights.

[Table 7] Table 3 List of markers used to identify various immune cells used in flow cytometry Mark TIL CD45 lymphocytes CD3 T cells CD8 cytotoxic T cells CD11c dendritic cells CD19 B cells

[Table 8] Table 4 Average values of positive cell rates of various immune cells infiltrating pancreatic cancer tissue Group 1 (control antibody administration group) Group 2 (IL-6R antibody administration group) Group 3 (PD-L1 antibody administration group) Group 4 (IL-6R antibody + PD-L1 antibody combined administration group) Group 5 (IL-6R antibody + PD-L1 antibody + gemcitabine combined administration group) Average positive cells (%) CD45+ 40.82 73.29 49.32 87.09 54.47 CD3+ CD45+ 17.80 30.57 19.02 46.53 30.17 CD8+ CD45+ 2.09 2.27 13.59 13.17 10.60 CD11c+ CD45+ 1.62 2.36 0.49 4.09 5.67 CD19+ CD45+ 3.81 9.72 3.91 6.44 22.38 CD45-positive cells, CD3-positive, CD45-positive cells, CD8-positive, CD45-positive cells, CD11c-positive, CD45-positive cells, and CD19-positive, CD45-positive cells infiltrating pancreatic cancer in KPΔC mice obtained by flow cytometry Average value of positive cell ratio of positive cells [Example 6]

Example 6-1 Combination therapy of anti-IL-6R antibody + anti-PD-L1 antibody + gemcitabine (G): Confirmation of antitumor effect in a transgenic mouse model of natural onset of pancreatic cancer (KPΔC mice) (growth marker: Ki67 and pErk)

Anti-IL-6R antibody + anti-PD-L1 antibody + gemcitabine (G) combined with The effect of the tumor effect.

As described in Example 5, to the transgenic mouse model of natural onset of pancreatic cancer (KPΔC mice), the mice were intraperitoneally administered with isotype IgG antibody, anti-IL-6R antibody, anti-PD-L1 antibody alone or in combination Antibodies, gemcitabine. The combination of administration is shown below: group 1 (control administration group) administration of isotype control IgG antibody, group 2 (IL-6R antibody administration group) administration of anti-IL-6R antibody, group 3 (PD-L1 antibody administration group) administration. group) anti-PD-L1 antibody, group 4 (IL-6R antibody + PD-L1 antibody combined administration group) combined with anti-IL-6R antibody and anti-PD-L1 antibody, and group 5 (IL-6R antibody +PD-L1 antibody + gemcitabine concomitant administration group) and three doses of anti-IL-6R antibody, anti-PD-L1 antibody and gemcitabine were administered in combination.

The pancreas containing pancreatic cancer was removed, fixed in 4% (wt/vol) buffered paraformaldehyde overnight at room temperature, and embedded in paraffin. Pancreatic cancer tissue sections with a thickness of 3 μm were cut from FFPE blocks to prepare slides containing pancreatic cancer tissue sections, and were subjected to hematoxylin/eosin (H/E) staining, Sirius red staining, or Ki67 and Immunohistochemical staining (IHC) for p-ERK. The following antibodies were used in IHC: p-ERK1/2 (Cell Signaling Technology; 1:100), Ki67 (Abeam; 1:1000). The staining signal was visualized by the avidin-biotin peroxidase method using a 3,3'-diaminobenzidine substrate (DAB) kit (Vector Laboratories). The specificity of staining was confirmed for each antibody by omitting control experiments with primary antibodies. Bright field images were acquired using a Zeiss Axio1 camera unit equipped with an AxioCam HRc (Zeiss) camera. Quantitative image interpretation of IHC staining in pancreatic cancer tissue was performed using Aperio ImageScope Software. The ratio calculated by dividing the number of positive nuclei for each growth marker by the total number of nuclei was the positive rate of Ki-67 and p-ERK, and was expressed in the form of mean ± standard deviation. Intergroup comparisons were made by two-sided Student's t-test. Statistical significance was set as *P<0.05, **P<0.01.

As shown in Fig. 9, the growth marker Ki-67 in the tumor tissue of the IL-6R antibody + PD-L1 antibody + gemcitabine combined administration group was 7.1%, which was statistically significant compared with the control administration group (19%). meaningful inhibition. Similarly, the growth marker p-ERK in the tumor tissue of the IL-6R antibody + PD-L1 antibody + gemcitabine combined administration group was 14.4%, which was statistically significant compared with the control administration group (25.2%). inhibition (Table 5).

In conclusion, the positive rates of tumor cell growth markers Ki-67 and p-ERK were significantly reduced by the combined treatment of IL-6R antibody + PD-L1 antibody + gemcitabine. It was found that the combined use of anti-IL-6R antibody and anti-PD-L1 antibody with the chemotherapeutic agent gemcitabine exerted a synergistic effect that could not be obtained by any single or combined drug, showing a significant anti-tumor effect. It is concluded that this result contributes to the excellent antitumor effect shown in Example 6-2.

[Table 9] Table 5 The average value of the ratio of growth marker Ki67 and pErk-positive nuclei in pancreatic cancer tissue of KPΔC mice obtained by IHC staining analysis Group 1 (control antibody administration group) Group 2 (IL-6R antibody administration group) Group 3 (PD-L1 antibody administration group) Group 4 (IL-6R antibody + PD-L1 antibody combined administration group) Group 5 (IL-6R antibody + PD-L1 antibody + gemcitabine combined administration group) Average positive nuclei (%) Ki-67 18.96 14.41 9.65 8.78 7.08 p-ERK1/2 25.21 17.12 22.35 16.32 14.39

Example 6-2 Anti-IL-6R Antibody + Anti-PD-L1 Antibody + Gemcitabine (G) Combination Therapy: Confirmation of Anti-tumor Effect Evaluation in Pancreatic Cancer Natural Onset Transgenic Mouse Model (KPΔC Mice) (by MRI Assessed tumor volume reduction)

As described in Example 5, KPΔC mice were administered with isotype control antibody, anti-IL-6R antibody, anti-PD-L1 antibody, gemcitabine alone or in combination, followed by tumor volume assessment by magnetic resonance imaging (MRI) . The administration group was the same as that described in Example 6-1. KPΔC mice started MRI experiments at 28-35 days of age and were repeated weekly (Ruess et al., Nat Med. 2018 Jul; 24(7): 954-960). Specifically, sedation was performed by continuous inhalation of 2% isoflurane in _O2 (Abbott) using a veterinary anesthesia device (Pentland Medical). In order to maintain the body temperature of the mice under anesthesia, it was properly monitored, and ophthalmic ointment was used for eye protection. Using a microscope surface coil in a 3.0T medical device (PHILIPS) and a multi-layer T2-weighted fast spin echo sequence in the axial direction (resolution: 0.3×0.3×0.7 mm ³ , 30 slices, echo time = 90 ms, repetition time > 3 s) for image collection. Solid tumor volume was calculated by adding the volume of truncated pyramids between tumor areas on adjacent sections using the OsiriX Lite DICOM Viewer.

Based on the volume of the pancreas containing pancreatic cancer at the start of administration (baseline), the ratio of the above-mentioned increase rate of the volume of the pancreas containing pancreatic cancer was calculated in %, plotted for each mouse, and compared between administration groups , it was found that as shown in Figure 10, the combined treatment of anti-IL-6R antibody + anti-PD-L1 antibody + chemotherapy gemcitabine significantly inhibited the volume of pancreas containing pancreatic cancer in almost all mice compared to any other treatment group The effect of increasing the ratio. The mean pancreatic volume change rate from baseline in the IL-6R antibody + PD-L1 antibody + gemcitabine administration group was 37.15%, compared with the IL-6R antibody + PD-L1 antibody combined administration group (167.33%) and the control administration group (183.07%), the tumor growth inhibitory effect was clearly confirmed (Table 6).

Furthermore, as a result of this study, it was newly discovered that three doses of anti-IL-6R antibody + anti-PD-L1 antibody combined with standard chemotherapy gemcitabine were administered compared to two doses of anti-IL-6R antibody + anti-PD-L1 antibody in combination. Concomitant administration can exert more anti-tumor effect, significantly suppress the increase in the volume of pancreas including pancreatic cancer, and its effect exceeds that of the prior art (Non-Patent Document 1: Mace TA. et al., Gut. 2018 Feb; 67(2) : 320-332) reported the combined effect of anti-IL-6R antibody + anti-PD-L1 antibody.

According to previous literature, there was no antitumor effect when gemcitabine was administered alone to the KPΔC mice (Wörmann et al., Gastroenterology. 2016 Jul; 151(1): 180-193), so it was confirmed that by anti-IL-6R antibody The use of gemcitabine in combination with anti-PD-L1 antibody exerts a synergistic effect that cannot be achieved by single administration or other combined use, showing a significant anti-tumor effect.

To sum up, it is proved that the combination therapy of anti-IL-6R antibody + anti-PD-L1 antibody and the standard chemotherapy of pancreatic cancer gemcitabine exerts an excellent synergistic effect that cannot be achieved by the prior art, and shows a significant anti-tumor effect. An epoch-making discovery.

[Table 10] Table 6 Mean value of the rate of change from baseline in the volume of pancreas containing pancreatic cancer in KPΔC mice obtained by MRI Group 1 (control antibody administration group) Group 2 (IL-6R antibody administration group) Group 3 (PD-L1 antibody administration group) Group 4 (IL-6R antibody + PD-L1 antibody combined administration group) Group 5 (IL-6R antibody + PD-L1 antibody + gemcitabine combined administration group) Average pancreatic volume change rate (%) 183.07 130.36 169.14 167.33 37.15

Example 6-3 Clinical increase of PD-L1 positive cancer cells by anti-IL-6R antibody In Example 6-2, the combination therapy of anti-IL-6R antibody + anti-PD-L1 antibody + gemcitabine (G) was confirmed Antitumor effect on natural onset transgenic mouse model of pancreatic cancer (KPΔC mice). It was verified that the anti-IL-6R antibody + anti-PD-L1 antibody + gemcitabine (G) + nab-paclitaxel (N) combination therapy can exert the same anti-tumor effect on human pancreatic cancer.

In the "Phase I clinical trial of tocilizumab and gemcitabine-nab-paclitaxel combination therapy for metastatic pancreatic cancer unresponsive to gemcitabine and nab-paclitaxel" described in Example 1 (EPOC1804), a patient After informed consent, the pancreatic cancer tissue was collected from the patient's liver metastases using an 18-gauge needle before the administration of GN+TCZ on day 0 (pre) and after the administration of the drug on day 28 (post), and immediately used 10% Neutral formalin fixation. Within 48 hours, the formalin-fixed needle biopsy tumor specimens were dehydrated and embedded in paraffin to prepare tumor specimen blocks (FFPE blocks). For the 7 cases other than the cases in which it was judged to be unsuitable for the analysis of the changes in the tumor microenvironment before and after GN+TCZ administration and the cases in which the specimen after GN+TCZ administration could not be obtained, the tumor microenvironment of pancreatic cancer liver metastases was analyzed by the following method Changes in PD-L1 expression.

Using a microtome, a thin section of tumor tissue with a thickness of 4 μm was cut from the FFPE block of the tumor specimen, and attached to a glass slide to prepare a tumor section specimen. The tumor sections were subjected to immunohistochemical fluorescence multiplex staining using 15 primary antibodies that recognize proteins of various immune cells (Gerdes. MJ et al. PNAS 110, 11982-11987 (2013)). Immunohistochemical fluorescence multiplexing assays have the advantage of having the same staining properties as standard immunohistochemical staining and the direct simultaneous comparative assessment of multiple biomarkers on the same cell, thereby allowing the identification of specific cell clusters. A pair of primary antibodies directly conjugated to two cyanochrome labels (Cy3, Cy5) was used to perform immunostaining according to each staining round, and a fluorescent immunostaining image of the staining in each round was obtained. After each cycle, the pigment label is inactivated, whereby a plurality of staining cycles are repeatedly performed on one tumor section specimen, and finally multiple staining data are obtained by superimposing the image analysis of each staining data. Specifically, using the 15 primary antibodies shown in Table AA, specific cell populations were identified by the combination of markers shown in Table BB. The following antibodies were used as primary antibodies in immunohistochemical fluorescence multiplex staining: CD15 (clone Carb-3, Dako), HEPATOCYTE ANTIGEN (clone OCH1E5, Abcam), CK-19 (clone A53-B/A2, Abcam) ), CD3 (clone F7.2.38, Dako), CD4 (clone EPR6855, Abcam), CD8 (clone C8/144B, Dako), CD14 (clone EPR3652, Abcam), α-SMA (clone 1A4, Sigma-Aldrich), PD-L1 (Collection SP263, Ventana), Collagen IV (Collection EPR20966, Abcam), CD31 (Collection 89C2, Cell Signaling Technologies), FOXP3 (Collection 206D, BioLegend), PD-1 (Collection 89C2, Cell Signaling Technologies) EPR4877, Abcam), Ki67 (SP6, Abcam), CD68 (KP1, BioLegend) were cloned. [Table 11] Table AA List of staining cycles for immunohistochemical fluorescence multiplex staining Round Cy3 Cy5 1 CD15 PD-L1 2 HEPATOCYTE ANTIGEN COLLAGEN IV 3 CK-19 CD31 4 CD3 FOXP3 5 CD4 PD-1 6 CD8 Ki67 7 CD14 CD68 8 α-SMA [Table 12] Table BB Summary of specific cell clusters identified by various combinations of staining markers co-expression phenotype CD3+CD4+ helper T cells CD3+CD4+FOXP3+ regulatory T cells CD3+PD-1+ T cells expressing PD-1 CD3+CD8+ cytotoxic T cells CD3+CD8+PD-1+ Down-regulated/disabled cytotoxic T cells CD3+CD8+Ki67+ Cytotoxic T cells in growing state CD68+PD-L1+ Macrophages expressing PD-L1 CD3+CD4+Ki67+ helper T cells in growth state PD-L1+CK-19+ Tumor cells expressing PD-L1 CK-19+Ki67+ growing tumor cells α-SMA+Ki67+ SMA-positive cells in growth state α-SMA+PDL1+ SMA-positive cells expressing PD-L1 CD31+Ki67+ CD31 positive cells in growth state CD68+Ki67+ growing macrophage HFPATOCYTE ANTIGEN HERATOCYTE COLLAGEN IV Collagen (Intercellular Matrix)

The tumor region as the CK-19 positive region in each tumor section was identified, and the average number of cells per ^mm2 in the ROI for each specific cell included in a plurality of evaluation regions (Region of Interest; ROI) was calculated. Mean values of specific cell densities for each tumor area are presented as mean ± standard error. Intergroup comparisons were made by Wilcoxon test. Fluorescence staining images were analyzed using NeoVUE or ImageJ software. Hematoxylin-eosin (H/E) staining of adjacent tumor sections was performed to obtain the overall image of the tumor area and the tissue structure of immune cells at the light microscope level. These results are shown in FIG. 13 .

It can be seen that regardless of the therapeutic effect shown in Example 1, the average value of the PD-L1-positive tumor cell density (number per mm ² ) in the tumor tissue before the administration (pre) was 69.04. After the injection (post) was 239.27, an increase of 246.57% compared with that before the injection. P=0.0845 in the Wilcarson test, confirming a significant increase. Based on this, the following conclusions are drawn: After GN+TCZ administration, the immune effect on the tumor is suppressed due to the hyperactivity of the immune checkpoint caused by the hyperactivity of PD-L1 expression in cancer cells.

Regardless of the therapeutic effect shown in Example 1, the ratio of phosphorylation of STAT3, a factor downstream of IL-6 signaling in tumor tissue (phosho-STAT3), was significantly higher after GN+TCZ administration (0.018%) than before administration (0.031%). It was reduced by 41.94% (p=0.0832). It is well known that inhibition of STAT3 phosphorylation is a biomarker of TCZ. Therefore, the effect of GN+TCZ administration was clearly confirmed in the obtained tumor specimens ( FIG. 14 ).

Based on these results, it is basically impossible to see the phenomenon of PD-L1 expression on tumor cells of GN non-responsive patients, and the expression of PD-L1 is significantly increased after GN + TCZ administration, which confirms that TCZ combined administration produces unexpected effects. . 15 shows the analysis results of immunohistochemical fluorescence multiplex staining of samples derived from the subjects (GAPO1) shown in Example 2 and Example 3. FIG. Arrows in the figure indicate PD-L1 positive cancer cells.

In conclusion, it is confirmed that GN+TCZ therapy induces PD-L1 hyperactivity in pancreatic cancer and induces tumor immune checkpoints, revealing evidence in human clinical practice by using the anti-PD-L1 antibody atezolizumab as an immune checkpoint. The representative immune checkpoint inhibitor is used in combination with GN+TCZ therapy to exert an antitumor effect that cannot be achieved by GN+TCZ combination therapy or single therapy.

Summary of existing data suggests that increased PD-L1 expression in tumor tissue contributes to the enhanced efficacy of the immune checkpoint inhibitor atezolizumab (Background Art). It was confirmed that PD-L1-positive cancer cells increased in tumor tissue samples collected from pancreatic cancer liver metastases of patients after administration of GN+TCZ, and the phosphorylation of STAT3, a factor downstream of IL-6 signaling in these tissues, was significantly inhibited , thus confirming the effect of TCZ. These results suggest that GN+TCZ therapy induces immune checkpoints in tumors, revealing evidence that by supplementing GN+TCZ therapy for human pancreatic cancer with the immune checkpoint inhibitor atezolizumab, resistance that cannot be achieved by administration alone or in other combinations can be achieved Basis for tumor effect. [Example 7]

Example 7 To study the efficacy and safety of multiple immunotherapy-based concomitant therapies in patients with metastatic pancreatic ductal adenocarcinoma without a history of systemic therapy. Multicenter, unblinded, randomized, Ib / Phase II umbrella trial (MORPHEUS-PANCREATIC CANCER).

This phase Ib/II open-label, multicenter, randomized trial was designed to evaluate the efficacy, safety, and pharmacodynamics of immunotherapy-based concomitant therapy in enrolled patients with metastatic pancreatic ductal adenocarcinoma (PDAC). . The specific purpose of the test and the corresponding evaluation items are briefly described below.

[Table 13-1] main purpose of effectiveness Corresponding assessment items l Evaluate the effectiveness of concomitant immunotherapy in clinical trial treatments l During the treatment period of the clinical trial, the objective remission (definition: complete remission or partial remission) determined by RECIST v1. secondary purpose of effectiveness Corresponding assessment items l Evaluate the effectiveness of concomitant immunotherapy in clinical trial treatments l PFS (definition: PFS between randomization and first disease progression or any preceding event of death from any cause) based on RECIST v1.1 Time) l OS after randomization (definition: time from randomization to death from any cause) l OS at a specified time point (eg 6 months) (Assistant Investigator) l Relative to study (Associate Study) Those based on the DOR (defined as the time between the first confirmed objective response to disease progression or any preceding event of death from any cause) in clinical trial treatment as determined by RECIST v1. A study (assistant study) with a written record of the time to onset of an objective tumor shrinkage effect based on disease control as determined by RECIST v1.1 (definition: stable for more than 12 weeks, or complete remission or partial remission)

[Table 13-2] Exploring Purpose of Effectiveness Corresponding assessment items l Evaluate the effectiveness of concomitant immunotherapy in clinical trial treatments l Study (assistant study) based on iRECIST-judged objective response l Study (assistant study) based on iRECIST-judged post-randomized PFS l Study (assistant study) based on iRECIST-judged DOR l Study (assistant study) The amount of change from baseline to subsequent time points in CA19-9 based on disease control determined by iRECIST security purpose Corresponding assessment items l Evaluate the safety of concurrent immunotherapy in clinical trial treatments l The occurrence rate, nature and severity of adverse events and abnormal clinical examination values. Severity was determined according to the National Cancer Institute's General Terminology Criteria for Adverse Events, Version 4.0. l Changes from baseline in vital signs and electrocardiogram (ECG) parameters l Changes from baseline in target clinical examination values Exploratory Purpose of Pharmacokinetics Corresponding assessment items l Identify the characteristics of the pharmacokinetic profile (PK profile) of the drug administered as part of the concurrent immunotherapy in the clinical trial treatment l Plasma or serum concentration of each agent (appropriate) at a specific time point l Assess the potential relationship between exposure to an agent in a clinical trial treatment and the efficacy and safety of concomitant immunotherapy l The relationship between the plasma concentration or serum concentration or PK parameter of each drug (appropriate based on the obtained data) and the efficacy evaluation items l The plasma concentration or serum concentration or PK parameter of each drug (appropriate based on the obtained data) ) and the relationship between safety assessment items ADA=anti-drug antibody; DOR=period of remission; iRECIST=modified RECIST v1.1 for immunotherapy; OS=overall survival; PFS=progression-free survival; PK=pharmacokinetics; Benchmark Note: Overall efficacy at a single time point was assessed by the investigator (assistant investigator) using RECIST v1.1. The total efficacy based on iRECIST was not recorded on the eCRF, and was calculated by the sponsor based on the individual lesion data assessed by the researcher (assistant researcher) and recorded on the eCRF.

Trial Design The trial consisted of patients with no history of systemic therapy for metastatic PDAC, and eligible patients were randomly assigned to either the control group [chemotherapeutic agent: gemcitabine + nab-paclitaxel (Gem/Nab-pac)] or the trial Any of the drug groups [Atezo + Chemo + TCZ for atezolizumab (Atezolizumab, Atezo) combined with a chemotherapeutic agent (Atezo + Chemo + TCZ)] (see Figure 11 for an overview).

Atezo+Chemo+TCZ test drug group was enrolled in two phases (preparatory phase and second expansion phase). In order to ensure a sufficient number of patients with high C-reactive protein values and to facilitate benefit-risk assessment in this part of the population, about 30 patients were enrolled in the preliminary phase. When clinical effects were observed in the Atezo+Chemo+TCZ group in the preliminary phase, about 25 patients were added to the administration group in the expansion phase. In order to maintain the balance of demographic characteristics and baseline characteristics with respect to potential predictive biomarkers, etc. between the administration groups, and to achieve further partial population analysis, additional patient enrollment may be allowed. During randomization, taking into account the specific exclusion criteria of the Atezo+Chemo+TCZ group, the randomization rate assigned to the control group should not exceed 35%.

For patients in the comparator arm, dosing was continued until disease progression was confirmed based on unacceptable toxicity or Response Criteria in Solid Cancer Version 1.1 (RECIST v1.1). For patients in the experimental drug group, comprehensively evaluate the data of X-ray image examination and biochemical examination, the results of local biopsy (if available), and clinical status (such as the deterioration of symptoms such as pain caused by the disease), and continue to implement the following table. Administration as briefly described in A until confirmation of unacceptable toxicity or loss of clinical benefit judged by the study (assistant study). T-cell responses induced by atezolizumab and other cancer immunotherapies (CITs) cause immune cell infiltration with the potential for initial tumor growth (called pseudomalignancy). Therefore, based on RECIST v1.1 Progress seen on radiology sometimes does not represent true disease progression. If no unacceptable toxicity is identified, patients who meet the criteria for disease progression according to RECIST v1.1 during the course of CIT concomitant therapy are allowed to continue treatment if they meet the following criteria. ● The researcher (assistant researcher) judges that there is evidence of clinical benefit after reviewing all the data obtained ● Symptoms and signs that clearly indicate disease progression (including clinical examination values such as new findings or worsening of hypercalcemia) have not been observed ● No deterioration in daily performance status of ECOG, generally believed to be caused by disease progression, was observed ● No observed tumor progression (eg, leptomeningeal disease) in important anatomical sites that cannot be managed by medical intervention approved in the clinical trial implementation plan

[Table 14] Table A Treatment regimen of Atezo+Chemo+TCZ group cycle length Dosage, route of administration, and regimen (drugs are displayed in the order of administration) 28 days • Tocilizumab 8 mg/kg iv on Day 1 of each cycle • Atezolizumab 1680 mg a iv on Day 1 of each cycle • nab-paclitaxel on Day 1, 8 and 15 iv at 125 mg/m ² b • Gemcitabine 1000 mg/m ² iv on Days 1, 8 and 15 of each cycle Atezo+Chemo+TCZ=atezolizumab+chemotherapy (nab-paclitaxel and gemcitabine)+tocilizumab; nab-paclitaxel=nanoparticle nab-paclitaxel a: On Day 1 of the first two cycles, intravenous tocilizumab Atezolizumab was administered 2 hours after the end of benzumab. On Day 1 of the subsequent cycle, after the intravenous injection of tocilizumab is completed, atezolizumab can be administered according to the instructions recorded in the clinical trial implementation plan. b: nab-paclitaxel was administered after the end of intravenous atezolizumab.

Safety evaluation period In order to confirm the possibility of overlapping toxicity in the Atezo+Chemo+TCZ group, after about 6 patients were enrolled, enrollment was suspended for safety evaluation. The therapeutic agents were administered more than once in at least one complete cycle (ie, each agent was administered in combination), and safety assessments were performed based on safety data obtained from more than 6 patients who completed safety follow-up evaluations. When it is judged that the combined therapy is sufficiently safe, the group will be opened again.

Assessment and Monitoring Throughout the clinical trial, all patients were closely monitored for adverse events, classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0). Tumor assessments were performed at 6-week intervals for the first 48 weeks (starting on Day 1 of Cycle 1), followed by 6- or 12-week intervals thereafter. The researcher (assistant researcher) used RECIST v1.1 to evaluate the effect. Based on the individual lesion data as assessed by the investigator (assistant investigator), the sponsor determined the response based on the modified RECIST v1.1 (iRECIST) for immunotherapeutics by program adjudication.

Selected Criteria Enrollment Criteria Patients who meet all of the following criteria are eligible for clinical trial treatment.

[Table 15] Patients over 18 years of age as of the time point signed on the consent form Patients with ECOG daily performance status of 0 or 1 Patients with histologically or cytologically diagnosed metastatic PDAC By evaluating histopathological examination data, Combined with clinical data and X-ray image data, metastatic PDAC was diagnosed. Patients with endocrine or acinar pancreatic carcinoma of the pancreas are not eligible to participate in this clinical trial. Patients with a history of systemic treatment without PDAC (assistant research) judged that patients with a survival period of more than 3 months can obtain representative tumor samples suitable for PD-L1 and/or additional biomarker judgment by national testing institutions. Collect baseline tumor tissue samples. Ideally, the specimen collection is performed by biopsy performed at the time of clinical trial enrollment. When the researcher (assistant researcher) cannot judge that the biopsy cannot be performed, the preserved tumor tissue is the tissue collected in the biopsy performed within 3 months before the enrollment, and the patient has not received anticancer therapy after the biopsy , after obtaining the permission of the Medical Monitor (Medical Monitor), the preserved tumor tissue can be submitted. Formalin-fixed paraffin-embedded tumor mass specimens (recommended), or more than 16 slides containing unstained freshly cut serial sections, and related pathological examination reports must be submitted. When only 10 to 15 slides are obtained, the patient may still participate in this trial after obtaining the permission of the medical monitor. Patients judged by the researcher (assistant researcher) to be able to comply with the clinical trial implementation plan Patients with measurable lesions (at least 1 target lesion) based on RECIST v1.1 Lesions with a history of radiation exposure are confirmed only at the site after exposure Deemed measurable lesions are permitted until definite progression is reached. Patients with sufficient hematological function and end-organ function as specified by the following clinical examination results. It is stipulated that the clinical examination results are obtained within 14 days before the start of administration of the clinical trial drug. − ANC 1.5×10 ⁹ /L (1500/μL) or more. It is stipulated that the administration of granulocyte colony-stimulating factor is not allowed within 14 days before the clinical examination during the screening period. − The number of white blood cells is more than 2.5×10 ⁹ /L (2500/μL) − The number of lymphocytes is more than 0.5×10 ⁹ /L (500/μL) − The number of platelets is more than 100×10 ⁹ /L (100,000/μL). It is stipulated that no blood transfusion shall be accepted within 7 days before the clinical examination during the screening period. − Blood transfusions may also be given to patients to meet this benchmark after consultation with a medical monitor for hemoglobin levels above 90 g/L (9.0 g/dL). − AST, ALT and ALP are below 2.5 × upper limit of normal (ULN). The following exceptions apply. Patients with confirmed liver metastases: AST and ALT below 5×ULN Patients with confirmed liver metastases or bone metastases: ALP below 5×ULN − Serum bilirubin below 1.5×ULN. The following exceptions apply. Patients with known Gilbert disease: serum bilirubin value below 3×ULN − creatinine clearance rate above 50 mL/min (calculated by Cockcroft-Gault formula) − serum albumin 25 g/L (2.5 g/dL) - Patients not on anticoagulation therapy: International normalized ratio (INR) or activated partial thromboplastin time (aPTT) less than 1.5×ULN patients on anticoagulation therapy: Anticoagulation Dosing regimen of the drug Stable patients with biopsy-capable tumors For women capable of pregnancy: As indicated in each dosing group, agree to remain abstinent (avoid heterosexual intercourse) or use contraception, and agree not to donate eggs; for Patient males: As indicated in each administration group, agree to remain abstinent (avoid intercourse with the opposite sex) or use contraception, and agree not to donate sperm

Exclude benchmarks Patients meeting any of the following criteria were excluded from clinical trials.

[Table 16-1] Patients with a history of administration of T-cell co-stimulators or immune checkpoint inhibitors (anti-CTLA-4 antibody drugs, anti-PD-1 antibody drugs, and anti-PD-L1 antibody drugs, etc.); before starting the administration of clinical trial drugs28 Patients who have received clinical trial treatment within days Patients whose adverse events did not improve to below Grade 1 on prior anticancer therapy. However, alopecia regardless of grade and peripheral neuropathy below Grade 2 are excluded. Only suitable for patients in the control group Uncontrolled tumor-related pain in patients with poorly controlled pleural, pericardial, or ascites requiring repeated (ie, multiple monthly) drainage ・Patients who need narcotic analgesics must have a stable dosing regimen at the time of trial enrollment. ・Symptomatic lesions that can be treated with palliative radiation therapy (such as bone metastases or metastases causing nerve entrapment) should be treated before starting the administration of the clinical trial drug. Patients need to recover from the effects of radiation. The minimum required withdrawal period is not specified. ・For asymptomatic metastatic lesions that are likely to cause functional disability or intractable pain if further growth (such as current epidural metastases without spinal cord compression), when appropriate, treatment should be started at Investigate topical therapy before administering a clinical trial drug. Patients with symptomatic, untreated or active progressive CNS metastases Patients with a history of treatment for central nervous system disorders are eligible to participate if they meet all of the following criteria. − Lesions that can be measured based on RECIST v1.1 are outside the central nervous system. − No history of intracranial hemorrhage or spinal cord hemorrhage. − Metastases limited to the cerebellum or supratentorial regions (ie, no metastases to the midbrain, pons, medulla, or spinal cord). − No progression was observed after completion of CNS therapy until the time of screening brain scan. − The patient did not receive targeted radiation therapy within 7 days before the start of the clinical trial drug administration, or did not receive whole-brain radiation therapy within 14 days before the start of the clinical trial drug administration. − Continued use of corticosteroids for the treatment of CNS lesions is not required. Anticonvulsants are allowed to be administered in stable doses. Asymptomatic patients with new-onset CNS metastases identified at screening were eligible for the trial after radiation therapy or surgery without repeat screening brain scans. Poorly controlled hypercalcemia (ionized calcium >1.5 mmol/L, calcium >12 mg/dL, or corrected serum calcium >ULN), or patients with symptomatic hypercalcemia requiring continuous treatment with bisphosphonates ・Patients who are being administered bisphosphonates for other reasons (eg, bone metastases or osteoporosis) without a significant clinical history of hypercalcemia are eligible for this trial. Patients with a history of leptomeningeal disease Autoimmune disease or immunodeficiency (including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Patients with Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, or multiple sclerosis), or those with a history of related diseases. Furthermore, the following are exceptions. ・Patients with a history of autoimmune-related hypothyroidism who are undergoing thyroid hormone replacement therapy are eligible to participate in this trial. ・Patients with controlled type 1 diabetes who are on stable insulin therapy are eligible to participate in this trial. ・Patients with eczema, psoriasis, lichen simplex chronicus, or leukoplakia vulgaris (eg, patients with psoriatic arthritis except those with psoriatic arthritis) are eligible to participate in this trial if they meet all of the following conditions. • The rash area is less than 10% of the body surface area • Good disease control at baseline with only low-efficiency topical corticosteroids No need to use psoralen long-wave ultraviolet therapy, methotrexate, retinol, biological agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids in the past 12 months. Acute exacerbation of pre-existing disease

[Table 16-2] Patients with a history of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or those with active pneumonitis observed by chest CT at screening patient ・Patients with a history of radiation pneumonitis (fibrosis) in the irradiation field can participate. HIV-positive patients at screening or at any point prior to screening ・Unless not permitted by the laws of each country, patients who have not obtained a positive result in an HIV test in the past will be tested for HIV at the time of screening. Patients with active hepatitis B virus (HBV) infection (chronic or acute) defined as a positive hepatitis B surface antigen (HBsAg) test at screening positive ・Patients with a history of HBV infection or treatment history, defined as a negative HBsAg test at screening and a positive hepatitis B core antibody test, are eligible for this trial. Quantitation did not reach 500 IU/mL. Patients with active hepatitis C virus (HCV) infection defined as a positive HCV antibody test at screening and a positive HCV RNA test thereafter ・HCV RNA test is performed only for patients with positive HCV antibody test. Patients with clinically known major liver diseases (alcoholic hepatitis, liver cirrhosis, fatty liver disease and hereditary liver disease, etc.) patients with active tuberculosis Patients who have been admitted to hospital due to complications of infectious diseases, bacteremia or severe pneumonia (but not limited to) within 4 weeks before the start of clinical trial drug administration Patients who have received oral or intravenous antibacterial drugs within 2 weeks before the start of clinical trial drug administration ・Patients who have received prophylactic administration of antibacterial drugs (eg, to prevent urinary tract infection or exacerbation of chronic obstructive pulmonary disease) are eligible to participate in this trial. Major cardiovascular disease (heart disease, myocardial infarction or cerebrovascular attack, etc., assessed as grade II or above according to the New York Heart Association's cardiac function classification) within 12 months before the start of the clinical trial drug administration. , or patients with unstable arrhythmia or unstable angina pectoris within 3 months before the start of administration of the clinical trial drug Patients who have experienced bleeding or hemorrhagic events of Grade 3 or higher within 28 days before starting the administration of the clinical trial drug Patients with a history of allogeneic stem cell transplantation or solid organ transplantation Patients who have undergone major surgery for purposes other than diagnostic purposes within 4 weeks before the start of clinical trial drug administration, or patients who are expected to undergo major surgery in clinical trials Placement of central venous access catheters (eg, ports, etc.) is not considered major surgery and is allowed. Patients with a history of malignancy other than pancreatic cancer within 2 years before screening. Among them, appropriately treated cervical intraepithelial cancer, non-melanoma skin cancer, localized prostate cancer, non-invasive breast duct cancer, or stage I uterine cancer have a negligible risk of metastasis or death (e.g., 5-year overall survival rate exceeding 50%). 90%) except

[Table 16-3] Other diseases that contraindicate the use of clinical trial drugs, metabolic dysfunction, physical examination findings or clinical examination values observed may affect the interpretation of results or increase the risk of treatment complications for patients. Pregnant and lactating women, or patients planning pregnancy during clinical trials Potentially pregnant women must obtain a negative serum pregnancy test result within 14 days prior to starting the administration of the clinical trial drug. Patients who have received live attenuated vaccines within 4 weeks prior to the start of administration of the clinical trial drug, or who are expected to require reductions during the atezolizumab administration period or within 5 months after the last administration of atezolizumab. patients with live vaccine Patients with a history of severe allergic reactions to chimeric antibodies or humanized antibodies or fusion proteins Patients with a history of hypersensitivity to Chinese hamster ovary cell-producing products or recombinant human antibodies Patients with known allergies or hypersensitivity to any clinical trial drug or its additives Patients who have been administered systemic immunostimulatory drugs (including but not limited to interferon and interleukin 2) within 4 weeks or within 5 half-lives of the drug (whichever is longer) before the start of administration of the clinical trial drug Administered systemic immunosuppressive drugs (including but not limited to adrenal corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide and anti-tumor necrosis) within 2 weeks before the start of clinical trial drug administration factor alpha preparations), or patients who are expected to be administered systemic immunosuppressive drugs in clinical trials. Among them, the following exceptions. Patients who have received acute administration of low-dose systemic immunosuppressive drugs, or single-pulse administration of systemic immunosuppressive drugs (eg, 48-hour adrenal corticosteroids for Eligible to participate in this trial after permission. Patients who were administered mineralcorticoids (eg, fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency were eligible to participate in this trial . Patients with known central nervous system demyelinating disease or seizures Patients with a history of diverticulitis, chronic ulcerative lower gastrointestinal disease (eg, Crohn's disease, ulcerative colitis), or other symptomatic lower gastrointestinal disease that may lead to gastrointestinal perforation Patients judged by the researcher (assistant researcher) to have liver disease unrelated to the diagnosis of cancer as a pre-existing disease Current active infection, or recurrent bacterial, viral, fungal (except nail bed fungal infection), mycobacterial or other infectious disease (including but not limited to atypical mycobacterial disease, HBV, HCV and herpes zoster) patient with medical history In the event of a global pandemic or epidemic of infectious diseases, research and screening of active infectious diseases should be conducted in accordance with the guidelines of various countries or medical institutions, or the corresponding guidelines of specialized groups (such as the American Society of Clinical Oncology or the European Society of Clinical Oncology). Patients who have been diagnosed with active tuberculosis and positive chest X-rays as a result of purified protein derivative (PPD) skin test or tuberculosis blood test results within 3 months before the start of clinical trial drug administration Patients with a positive PPD skin test or blood test for tuberculosis but a subsequent negative chest X-ray may be eligible for this clinical trial. Untreated latent tuberculosis infection Active primary or secondary immunodeficiency, or patients with previous medical history ALT or AST over 1.5×ULN, or over 5×ULN in patients with liver metastases Patients with C-reactive protein exceeding 10 mg/dL

The main analysis of statistical methods is as specified in Table A, and the main evaluation item of effectiveness is the objective mitigation in the test. Patients with missing or unimplemented response determinations are non-responders. For each cohort, the ratio of patients who achieved complete or partial remission, the objective response rate (ORR), and its 90% confidence interval (Clopper-Pearson method) were calculated. The difference between the ORRs of the test drug group and the control drug group and its 90% confidence interval were also calculated. Confidence intervals were inferred using asymptotic normality based on the number of cases.

Results Compared with the standard treatment G+N, the 4-dose combination therapy of tocilizumab+atezolizumab+G+N showed higher clinical efficacy. More specifically, compared with the 2-dose combination therapy of nab-paclitaxel and gemcitabine, it shows a higher clinical efficacy. Moreover, as a group which shows clinical benefit, the C-reactive protein high value patient group can be mentioned. Furthermore, as another group showing clinical benefit, the phosphorylated STAT3 positive patient group can be mentioned.

Figure 1 shows an outline of the clinical trial design. Figure 2 shows the rate of change from baseline in the tumor marker CA19-9. Fig. 3 shows the production levels of α-SMA and phosphorylated STAT3 in tumor specimens before and after administration of GN+TCZ. FIG. 4 shows the concentration of the low-molecular-weight drug (levofloxacin was used as an indicator agent) in the tumor specimen before and after administration of GN+TCZ. Figure 5 shows the structure of a hemi-mechanical PK-PD model incorporating G, N, and TCZ regarding changes in neutrophil number. Baseline of neutrophil count (Base), circulating neutrophil count (CircNeut), drug effect of G or N (Drug_Effect), feedback parameter (FP), neutrophil disappearance rate constant (Kcirc), meter Michaelis-Menten constant (Km), neutrophil growth rate (kprol), rate constant (ktr), mean differentiation time (MTT), differentiation compartment (n), TCZ effect (TCZ_Effect), Maximum response speed (Vmax). Figure 6 shows the actual observed and predicted neutrophil counts. The 5th percentile, 50th percentile (solid line), and 95th percentile are shown as lines for the predicted results of neutrophil count. Using actual doses, 100 simulations were performed on 10 subjects. The number of neutrophils actually observed in the "Phase I trial of tocilizumab + gemcitabine/nab-paclitaxel (EPOC1804) in patients with metastatic gemcitabine/nab-paclitaxel resistance" is shown as a dot . Fig. 7 shows the simulation results of the evolution of the number of neutrophils when TCZ+GN is used together. 1000 simulations were performed according to the protocol shown below. Dosing regimen: 4 different doses of GN and GN+TCZ: 4 mg/kg once with 2-week intervals (Q2W), 8 mg/kg once with 2-week intervals (Q2W), 4 mg/kg once with 4-week intervals Weekly (Q4W), once at 8 mg/kg and 4 weeks apart (Q4W). Regarding the prediction result of the number of neutrophils (cells/mm ³ ), the prediction interval of the 5th to 95th percentiles was filled with color and displayed, and the 50th percentile was shown by the solid line in the center. The horizontal line of 1000 cells/mm ³ is the decrement reference. Fig. 8-1 shows the effect of promoting the infiltration of various immune cells into pancreatic cancer tumor tissue by IL-6 antibody + PD-L1 antibody + gemcitabine. Quantification of infiltrating cells positive for the following cell surface markers in pancreatic cancer of KPΔ(δ)C mice obtained by flow cytometric analysis: CD45 positive cells (A); CD3 positive and CD45 positive cells (B); CD8 Positive and CD45 positive cells (B); CD11c positive and CD45 positive cells (C); and CD19 positive and CD45 positive cells (D). Intergroup comparisons were made by two-sided Student's t-test. Statistical significance was set as *P<0.05, **P<0.01, ***P<0.001. A: Infiltration promotion of CD45-positive immune cells; B: Infiltration promotion of T cells (CD3-positive and CD45-positive cells; CD8-positive and CD45-positive cells). Figure 8-2 continues from Figure 8. C: Infiltration promotion of dendritic cells; D: Infiltration promotion of B cells. FIG. 9 shows the effect of suppressing the growth of pancreatic cancer tissue by anti-IL-6R antibody + anti-PD-L1 antibody + gemcitabine. Growth markers Ki67 and pErk signaling in KPΔC mouse pancreatic cancer tissues were quantified by IHC staining analysis. Results are presented as mean ± standard deviation. Statistical significance is based on two-sided Student's t-test (*P<0.05, **P<0.01). Figure 10 is an evaluation of tumor volume (pancreatic ductal adenocarcinoma (PDAC)) using anti-IL-6R antibody, anti-PD-L1 antibody, chemotherapeutic agent (gemcitabine), and their isochronous use. Pancreatic volume containing pancreatic cancer in each KPΔC mouse was assessed by MRI, and the rate of change was plotted using the volume at the start of administration as a baseline. Figure 11 shows an outline of the clinical trial design. Figure 12 is a diagram showing the standard chemotherapy for pancreatic cancer "The Algorithm of Pancreatic Cancer Chemotherapy" (translated from the Pancreatic Diagnosis and Treatment Guidelines 2019 Edition). Figure 13 is a comparison of the density of PD-L1 positive cancer cells before and after GN+TCZ administration. Figure 14 is a comparison of the positive area ratio of phosphorylated STAT3 in tumor tissue before and after GN+TCZ administration. 15 is an analysis of PD-L1-positive cancer cells based on immunohistochemical fluorescence multiple staining of samples derived from subjects (GAPO1) before and after GN+TCZ administration.

Claims (15)

A pharmaceutical composition, which contains an immunotherapy agent as an active ingredient, is used in combination with an IL-6 inhibitor and at least one chemotherapeutic agent to treat pancreatic cancer. The pharmaceutical composition of claim 1, wherein the chemotherapeutic agent is a pyrimidine-based agent selected from fluorouracil, tegafur, gemcitabine and capecitabine, and/or selected from paclitaxel, nab-paclitaxel and paclitaxel A taxane-based agent in the group, and/or a platinum-based agent selected from cisplatin and oxaliplatin. The pharmaceutical composition according to claim 1 or 2, wherein the above-mentioned IL-6 inhibitor is an anti-IL-6R antibody. The pharmaceutical composition according to any one of claims 1 to 3, wherein the immunotherapeutic agent is a PD-1/PD-L1 signaling inhibitor. The pharmaceutical composition of any one of claims 1 to 4, wherein the chemotherapeutic agent, the IL-6 inhibitor, and the PD-1/PD-L1 signaling inhibitor are administered simultaneously, separately, or sequentially. The pharmaceutical composition according to any one of claims 1 to 5, wherein the PD-1/PD-L1 signaling inhibitor is an anti-PD-L1 antibody. A medicine containing atezolizumab, which is used by the following method, the method comprising treating the medicine containing atezolizumab in combination with tocilizumab, gemcitabine and nab-paclitaxel Pancreatic cancer in a human subject administered the following dosages: (i) tocilizumab at a dose of 8 mg/kg once at 4-week intervals (Q4W); and atezolizumab Doses were selected from the group consisting of 840 mg once with a 2-week interval (Q2W), 1200 mg once with a 3-week interval (Q3W), and 1680 mg once with a 4-week interval (Q4W); (ii) Tocilizumab The dose of antibacterial was 4 mg/kg once with 2-week interval (Q2W); and the dose of atezolizumab was selected from 840 mg once with 2-week interval (Q2W), 1200 mg once with 3-week interval (Q3W), a cohort of 1680 mg once with a 4-week interval (Q4W); (iii) tocilizumab at a dose of 8 mg/kg once with a 2-week interval (Q2W); and atezolizumab The dose of the antifungal drug was selected from the group consisting of 840 mg once with 2-week interval (Q2W), 1200 mg once with 3-week interval (Q3W), and 1680 mg once with 4-week interval (Q4W); The dose of atezolizumab is 8 mg/kg once with a 4-week interval (Q4W); and the dose of atezolizumab is 1680 mg once with a 4-week interval (Q4W); and administered weekly for 3 consecutive weeks A single dose of nab-paclitaxel and gemcitabine hydrochloride was discontinued in the 4th week. The dose of nab-paclitaxel was 125 mg/m ² (body surface area) calculated as paclitaxel, and the dose of gemcitabine hydrochloride was calculated as 1000 mg once. /m ² (body surface area). A medicament containing an anti-PD-L1 antibody for administration in combination with an IL-6 inhibitor and a chemotherapeutic agent in the treatment of cancer to enhance the effect of the chemotherapeutic agent over previous treatments. A medicine containing an anti-IL-6 antibody and an anti-PD-L1 antibody for administration in combination with a chemotherapeutic agent in the treatment of pancreatic cancer to enhance the effect of the chemotherapeutic agent. The medicine of claim 8 or 9, wherein increasing the effect of a chemotherapeutic agent comprises: increasing the response rate, remission rate and/or disease control rate in a group comprising individuals in need of treatment of chemotherapeutic agent-resistant cancer. A composition comprising an IL-6 inhibitor and a PD-1/PD-L1 signaling inhibitor for promoting the penetration of a cancer therapeutic agent into cancer tissue when the cancer therapeutic agent is used to treat cancer in an individual. A composition containing a PD-1/PD-L1 signaling inhibitor, which is administered in combination with an IL-6 inhibitor, or contains an IL-6 inhibitor and is used to promote immune cell infiltration into target tissues. The composition of claim 12, wherein said immune cells are CD45 positive cells. The composition of claim 12 or 13, wherein said target tissue is an IL-6 overexpressing tissue. The composition of any one of claims 12 to 14, wherein the target tissue is a tumor tissue.

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