WO2020230792A1 - がん患者のペプチドワクチン療法に対する適格性を判定する方法 - Google Patents

がん患者のペプチドワクチン療法に対する適格性を判定する方法 Download PDF

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WO2020230792A1
WO2020230792A1 PCT/JP2020/019002 JP2020019002W WO2020230792A1 WO 2020230792 A1 WO2020230792 A1 WO 2020230792A1 JP 2020019002 W JP2020019002 W JP 2020019002W WO 2020230792 A1 WO2020230792 A1 WO 2020230792A1
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cancer
lck
peptide
patient
peptide vaccine
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French (fr)
Japanese (ja)
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伊東　恭悟
正典 野口
茂 由谷
七條　茂樹
山田　亮
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Priority to US17/610,300 priority patent/US20220233661A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56972—White blood cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • Non-Patent Documents 1 to 3 The results of a randomized phase II clinical trial of tailor-made peptide vaccine therapy have been partially reported in the past (Non-Patent Documents 4-9). In this clinical trial, longer overall survival (OS) was observed in patients with prostate and colorectal cancer who received tailor-made peptide vaccine therapy (Non-Patent Documents 4 and 5).
  • OS overall survival
  • Non-Patent Document 10 In a randomized, double-blind, placebo-controlled phase 3 clinical trial in patients with recurrent glioblastoma, there was no significant difference in OS between patients receiving tailor-made peptide vaccine therapy and those in the placebo group.
  • Non-Patent Document 11 a method for determining patient eligibility for cancer vaccine therapy for brain tumors using a tailor-made peptide vaccine is known (Patent Document 1).
  • One of the purposes of this disclosure is to determine the eligibility of cancer patients for peptide vaccine therapy.
  • the present inventors have found that the neutrophil ratio and / or the lymphocyte ratio of cancer patients correlates with their eligibility for peptide vaccine therapy.
  • it is a method of determining whether or not a cancer patient is eligible for peptide vaccine therapy, and is collected from the cancer patient about 7 to 35 days before the scheduled administration date of the peptide vaccine. Methods are provided that include determining whether the patient is eligible for peptide vaccine therapy based on the neutrophil ratio and / or lymphocyte ratio of the blood.
  • kits for determining whether a cancer patient is eligible for peptide vaccine therapy, including reagents for measuring neutrophil and / or lymphocyte ratios.
  • a peptide vaccine agent comprising at least one peptide antigen for treating cancer in a patient determined to be eligible for peptide vaccine therapy by the method described above is provided.
  • kits comprising at least one peptide antigen is provided for preparing a peptide vaccine for treating cancer in a patient who has been determined to be eligible for peptide vaccine therapy by the method described above.
  • kits comprising WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-109, Lck-208, PAP-213, Lck-486 and Lck-90 is provided.
  • kits comprising one or more polynucleotides, depending on the one or more polynucleotides, WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-109, Lck- Kits are provided in which 208, PAP-213, Lck-486 and Lck-90 are encoded.
  • kits are provided for preparing peptide vaccines comprising new combinations of peptide antigens or polynucleotides encoding them.
  • the flowchart of Consolidated Standards of Reporting Trials (CONSORT, integrated standard for clinical trial report) of Test Example 1 is shown.
  • the Kaplan-Meier curve for the overall survival time by the treatment of Test Example 1 is shown.
  • the relationship between the p-value of the interaction between the neutrophil ratio (A) and the lymphocyte ratio (B) of Test Example 1 and the number of patients is shown.
  • the numbers in the graph indicate the number of PPV groups that fit each cutoff value.
  • the patient group (Others) that meets the cutoff value of either or both of the neutrophil ratio ⁇ 64% and the lymphocyte ratio ⁇ 26% A comparison of median OS values between groups of patients who meet both neutrophil ratio ⁇ 64% and lymphocyte ratio ⁇ 26%, their hazard ratios and p-values are shown.
  • the correlation between the hazard ratio (HR) of overall survival (OS) and the neutrophil ratio on the study enrollment date in PPV therapy of Study Example 4 is shown.
  • the correlation between the HR of OS in the PPV therapy of Study Example 4 and the lymphocyte ratio on the date of enrollment is shown.
  • peptide vaccine therapy means a method for treating cancer by administration of a peptide vaccine agent.
  • Peptide vaccines include at least one peptide antigen.
  • peptide antigen means a peptide derived from a tumor-related antigen protein and for inducing a tumor-specific immune response. Peptide antigens are roughly classified into short-chain peptide antigens and long-chain peptide antigens according to the difference in chain length.
  • the peptide antigen may be, but is not limited to, chemically synthesized or isolated and purified from a biological sample. Examples of methods for chemically synthesizing peptides include the Fmoc method and the azide method.
  • peptide antigens isolated and purified from biological samples include peptide antigens produced by genetic engineering peptide synthesis.
  • the peptide antigen comprises a chemically synthesized short chain peptide antigen and / or a long chain peptide antigen.
  • the peptide antigen comprises a chemically synthesized short chain peptide.
  • short-chain peptide antigen means an epitope peptide having a chain length that can directly bind to MHC on the surface of an antigen-presenting cell.
  • the short-chain peptide antigen is 8 to 17 amino acid residues, which may be 8 to 11 amino acid residues for the purpose of inducing killer T cells, and may be 8 to 11 amino acid residues for the purpose of inducing helper T cells. May be 12 to 17 amino acid residues.
  • the short chain peptide antigen is an 8-10 or 9-10 amino acid residue.
  • long-chain peptide antigen means a peptide having a relatively long chain length containing one to a plurality of epitopes. Since long-chain peptide antigens cannot normally bind directly to MHC, they are taken up by antigen-presenting cells and processed into epitope peptides inside the cells by the action of proteases and peptidases in endosomes, proteasomes in the cytoplasm, and the like.
  • the long-chain peptide antigen the natural amino acid sequence of the tumor-related antigen protein may be used as it is, or an amino acid sequence in which a plurality of epitope peptides are artificially linked may be used.
  • the peptide vaccine agent comprises at least one peptide antigen selected from the peptide antigen group shown in Table 1 below.
  • Peptide vaccines may contain peptide antigens not listed in Table 1.
  • the peptide vaccine therapy may be "tailor-made peptide vaccine therapy".
  • "tailor-made peptide vaccine therapy” is also referred to as personalized peptide vaccine therapy or custom-made peptide vaccine therapy, and means a method for treating cancer by administration of a tailor-made peptide vaccine agent.
  • a tailor-made peptide vaccine agent means a peptide vaccine agent containing a peptide antigen individually selected based on the analysis result of the patient (tumor-related antigen expressed by the patient, tumor-specific immunoreactivity of the patient, etc.).
  • Tailor-made peptide vaccines include, but are not limited to, 1 to 7 peptide antigens, preferably 3 to 6 peptide antigens, and more preferably 4 peptide antigens.
  • the tailor-made peptide vaccine comprises at least one, preferably at least two, at least three, at least four, or up to four peptide antigens.
  • a peptide antigen group corresponding to a patient's HLA type is selected from a peptide antigen group defined for each HLA type, and the patient's immune response to each peptide antigen constituting the peptide antigen group is selected. It may contain at least one peptide antigen selected based on sex (eg, in order of increasing immunoreactivity).
  • the tailor-made peptide vaccine agent is for a group of peptide antigens corresponding to the HLA-A24, -A2, -A3 supertype (A3sup: -A3, -A11, -A31 or -A33) or -A26. It contains at least one peptide antigen selected based on immunoreactivity.
  • HLA is an abbreviation for human leukocyte antigen (Human Leucocyte Antigen) and means human major histocompatibility complex (MHC). HLA is roughly classified into class I antigen and class II antigen. Class I antigens are further divided into class Ia antigens (HLA-A, -B, -C) and class Ib antigens (HLA-E, -F, -G).
  • the type of HLA can be identified by conventional methods, for example by serological typing, cytological typing, or DNA typing.
  • the type of "HLA" of a patient is usually determined prior to preparation of the peptide vaccine, but is not limited to this. In certain embodiments, the HLA type may be further determined before, during or after the preparation of the peptide vaccine, or before, during or after the dosing cycle.
  • the immunoreactivity of a patient to a peptide antigen can be examined by an antibody test or the like using a sample obtained from the patient, for example, body fluid or blood (for example, whole blood, plasma or serum).
  • Antibody tests include, for example, methods that utilize enzyme-linked immunosorbent assay (ELISA), flow cytometers, or flow metric (also known as "Bead-based multiplex assays", also referred to as "fluorescent bead arrays").
  • ELISA enzyme-linked immunosorbent assay
  • flow cytometers for example, whole blood, plasma or serum
  • flow metric also known as "Bead-based multiplex assays"
  • the immunoreactivity measure is a quantitative value (mean) obtained with a placebo containing an adjuvant but not a peptide antigen plus 5 times the standard deviation (SD). If the value is larger than the value and larger than the integer closest to the value (mean value + 5 ⁇ SD), it may be determined that there is immunoreactivity. In other embodiments, immunoreactivity may be measured using flow cytometry or flow cytometry. In this example, if the signal level for the peptide antigen (eg, fluorescence intensity unit (FIU)) is less than 10 FIU, it is evaluated as unreacted or undetectable (ND: Not detected), and if it is 10 FIU or more, there is immunoreactivity. It may be evaluated as.
  • FEU fluorescence intensity unit
  • a patient's immune responsiveness to a peptide antigen is, for example, based on each peptide antigen (eg, a microtiter) so as to emit a particular level of signal (eg, 1000 FIU) to a particular positive sample (blood sample of known reactivity). It can be measured using a substrate immobilized on a plate or beads).
  • immunoreactivity involves contacting the substrate with a patient's blood sample, washing, and then contacting the substrate with a labeled substance (eg, a fluorescent substance) -labeled anti-human antibody (labeled secondary antibody). It can be measured by washing and then detecting a signal (eg, fluorescence) derived from the labeling substance from the substrate.
  • the level of the signal from the substrate eg, FIU
  • the level of the signal from the substrate eg, FIU
  • it may be evaluated as unreacted or undetectable, and if it is 10 FIU or more, it may be evaluated as immunoreactive.
  • the measurement of immunoreactivity is performed prior to the preparation of the peptide vaccine agent used in the initial dosing protocol. In other embodiments, immunoreactivity measurements may be further performed after the first dosing protocol and based on the results the peptide antigens to be included in the peptide vaccines used in the next dosing protocol may be selected.
  • the tailor-made peptide vaccine agent comprises at least one peptide antigen selected from the peptide antigen group shown in Table 1 above.
  • Tailor-made peptide vaccines may contain peptide antigens not listed in Table 1.
  • tailor-made peptide vaccines are SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-1293, Lck-486, Lck-488, PSMA-624, PTHrP- At least one peptide selected from 102, CypB-129, Lck-246, WHSC2-103, UBE-43, WHSC2-141, HNRPL-140, SART3-302, SART3-734, Lck-90 and Lck-449. Contains antigens.
  • the tailor-made peptide vaccines are SART2-93, SART3-109, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3-1293, SART2-161, Lck-486, Lck- It contains at least one peptide antigen selected from 488, PSMA-624 and PTHrP-102.
  • the tailor-made peptide vaccine is selected from WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-109, Lck-208, PAP-213, Lck-486 and Lck-90. Contains at least one peptide antigen.
  • the tailor-made peptide vaccine may comprise a peptide antigen corresponding to the patient's HLA type (eg, HLA-A24, -A2, -A3sup or -A26).
  • the patient is HLA-A24 positive and the peptide antigens are SART2-93, SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3-1293, SART2-161. , Lck-486, Lck-488, PSMA-624, EZH2-735, PTHrP-102, preferably selected from the group consisting of SART3-109, Lck-208, PAP-213 and Lck-486.
  • the patient is HLA-A2-positive and the peptide antigens are CypB-129, Lck-246, Lck-422, MAP-432, WHSC2-103, HNRPL-501, UBE-43, UBE-85, WHSC2-141, Selected from the group consisting of HNRPL-140, SART3-302 and SART3-309, preferably from the group consisting of WHSC2-103, CypB-129, UBE-43 and HNRPL-140; patients are HLA-A3, -A11.
  • peptide antigens from CypB-129, Lck-422, WHSC2-103, SART3-109, SART3-511, SART3-734, Lck-90, Lck-449 and PAP-248.
  • the peptide vaccine therapy may be "non-tailor-made peptide vaccine therapy".
  • “non-tailor-made peptide vaccine therapy” means a method for treating cancer by administration of a non-tailor-made peptide vaccine agent.
  • Non-tailor-made peptide vaccines include pre-determined peptide antigens rather than individually selected peptide antigens based on the patient's immune responsiveness to the peptide antigens.
  • the non-tailor-made peptide vaccine agent comprises at least one of the peptide antigens listed in Table 1.
  • the non-tailor-made peptide vaccine agent may contain any combination of the peptide antigens listed in Table 1 and may contain all the peptide antigens listed in Table 1.
  • the non-tailor-made peptide vaccines are SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-1293, Lck-486, Lck-488, PSMA-624, PTHrP.
  • the antigens may be included in any combination or all.
  • the non-tailor-made peptide vaccines are SART2-93, SART3-109, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3-1293, SART2-161, Lck-486, Lck.
  • Peptide antigens selected from -488, PSMA-624 and PTHrP-102 may be included in any combination or all.
  • the non-tailor-made peptide vaccine agent may comprise a peptide antigen corresponding to the patient's HLA type (eg, HLA-A24, A2, A3 supertype or A26).
  • the non-tailor-made peptide vaccine agent used for each HLA type patient may contain any combination or all of the peptide antigens corresponding to each HLA type shown in Table 1.
  • the patient is HLA-A24 positive and the peptide antigens are SART2-93, SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3-1293, SART2-161.
  • the patient is HLA-A2-positive and the peptide antigens are CypB-129, Lck-246, Lck- Selected from the group consisting of 422, MAP-432, WHSC2-103, HNRPL-501, UBE-43, UBE-85, WHSC2-141, HNRPL-140, SART3-302 and SART3-309; patients are HLA-A3, -A11, -A31 or -A33 positive, peptide antigens are CypB-129, Lck-422, WHSC2-103, SART3-109, SART3-511, SART3-734, Lck-90, Lck-449 and PAP- Selected from the group consisting of 248; or the patient is HLA-A26 positive and the peptide antigen is selected from the group consisting of MAP-432, WHSC2-103, HNRPL-501 and SART
  • Peptide vaccines are prepared according to conventional methods. Peptide vaccines can be prepared, but not limited to, by mixing the peptide antigen in powder or liquid form with a pharmaceutically acceptable carrier. In certain embodiments, the peptide vaccine may further comprise an adjuvant to enhance the specific immune response induced by the peptide antigen.
  • adjuvant means a substance or an auxiliary agent that enhances a specific immune response against a peptide antigen contained in a peptide vaccine agent by adding, mixing or co-administering the peptide vaccine agent.
  • Adjuvants are generally classified into two types: innate immune receptor activation type and delivery system type.
  • the innate immune receptor-activated adjuvant include substances derived from constituents of microorganisms such as bacteria, viruses, and fungi, or derivatives thereof.
  • the delivery system type adjuvant include mineral salts such as aluminum salts, water-oil emulsions, and liposomes.
  • Peptide vaccines include, but are not limited to, complex adjuvants that combine innate immune receptor-activated adjuvants and / or delivery system adjuvants.
  • the peptide vaccine can be administered by methods such as subcutaneous administration, intradermal administration, intramuscular administration, intravenous administration, nasal administration, and oral administration.
  • the peptide vaccine is administered to the patient by subcutaneous injection.
  • Peptide vaccines in injectable form can be prepared by conventional methods and are prepared by dissolving, but not limited to, peptide antigens in powder or liquid form in a pharmaceutically acceptable injection solvent.
  • the administration schedule and dose of the peptide vaccine can be appropriately set by those skilled in the art according to the patient's health condition, age, body weight, administration route, administration form, etc. so that the effective amount is administered to the patient.
  • the peptide vaccine may be administered once every 1, 2, 3, 4, 5 or 6 weeks.
  • the dosing schedule may include several cycles (eg, 2), including several (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) administrations of the peptide vaccine. 3, 4, 5, 6, 7, 8 cycles or more) can be included.
  • the interval and / or frequency of administration of the peptide vaccine during the cycle may be the same or different between cycles.
  • one cycle comprises 6 doses, the first cycle administers the peptide vaccine once a week and the second cycle administers once every two weeks. After the third cycle, it may be administered once every three weeks or more.
  • one cycle comprises six doses, the first cycle is administered once a week, and the second and subsequent cycles are administered once every two weeks.
  • one cycle comprises six doses, the first cycle is administered once a week, the second cycle is administered once every two weeks, and the second. In 3 cycles, it is administered once every 4 weeks, and after the 4th cycle, it is administered once every 4 to 12 weeks.
  • the peptide vaccine is administered four times a week in the first cycle, eight times every two weeks in the second cycle, and one every four weeks in the third cycle. It is administered 8 times at a frequency of once, and once every 4 to 12 weeks after the 4th cycle.
  • one cycle comprises four doses, the first cycle administers the peptide vaccine once a week, and the second cycle administers once every 4-8 weeks. , After the 3rd cycle, administer once every 4 to 12 weeks.
  • the peptide vaccine is administered six times a week in the first cycle and once every three weeks in the second and subsequent cycles.
  • one cycle comprises eight doses, in which the peptide vaccine is administered four times a week, then four times every two weeks, and the second. In the cycle, it is administered 4 times at a frequency of once every 2 weeks and then 4 times at a frequency of once every 4 weeks.
  • one cycle comprises four doses, in which the peptide vaccine is administered at a frequency of once every four weeks in the first and second cycles. In these embodiments, administration may be continued at a frequency of once every 2 to 12 weeks after the second cycle.
  • the dose of a single peptide vaccine for an adult is, for example, about 0.01 to 100 mg, about 0.1 to 50 mg, about 1 to 10 mg, about 2 to 8 mg, and about 3 to 6 mg per one peptide antigen. For example, it can be about 3 mg or about 6 mg.
  • the peptide vaccine agent may be a combination of compositions containing one or more peptide antigens, and all peptides. It may be a single composition containing an antigen. If the peptide vaccine is a combination of compositions, each composition may be administered to a separate site.
  • cancer patient means a person suffering from cancer.
  • the patient is HLA-A24, -A2, -A3sup or -A26 positive.
  • Cancers include, for example, lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma (liver cancer), head and neck. Partial cancer, sarcoma, esophageal cancer, kidney cancer or gastric cancer, but not limited to these.
  • the cancer is prostate cancer, lung cancer, breast cancer, colon cancer, stomach cancer, hepatocellular carcinoma, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer.
  • the cancer is prostate cancer, lung cancer, breast cancer, colon cancer, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer.
  • the cancer is prostate cancer, particularly castration-resistant prostate cancer, metastatic castration-resistant prostate cancer or docetaxel non-responsive prostate cancer.
  • the cancer is prostate cancer, lung cancer, breast cancer, colon cancer, stomach cancer, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer, and the determination is neutrophil. Perform based on the ratio.
  • the cancer is prostate cancer, lung cancer, breast cancer, colon cancer, hepatocellular carcinoma, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer. It is based on the lymphocyte ratio.
  • the cancer is prostate cancer, lung cancer, breast cancer, colon cancer, hepatocellular carcinoma, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer. It is based on the neutrophil ratio and the lymphocyte ratio.
  • the cancers are lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, head and neck cancer, sarcoma, esophageal cancer. Cancer or kidney cancer.
  • the cancers are lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, head and neck cancer, sarcoma, esophageal cancer. If you have cancer, kidney cancer or gastric cancer, make a judgment based on the neutrophil ratio.
  • the cancers are lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, head and neck cancer. If you have pancreatic cancer, esophageal cancer or kidney cancer, make a judgment based on the lymphocyte ratio.
  • the cancers are lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, head and neck cancer. If you have pancreatic cancer, esophageal cancer or kidney cancer, the judgment is based on the neutrophil ratio and lymphocyte ratio.
  • the blood used for measuring the neutrophil ratio and / or the lymphocyte ratio is collected from a cancer patient before administration of a peptide vaccine agent.
  • a cancer patient For example, it was collected from a cancer patient about 7 to 35 days before, about 10 to 28 days, about 14 to 28 days, or about 14 to 21 days before the scheduled administration date of the peptide vaccine.
  • Blood can be collected in the usual way, for example from a vein.
  • the "neutrophil ratio” is a percentage of the number of neutrophils to the number of white blood cells (that is, the total number of lymphocytes, neutrophils, eosinophils, basophils and monocytes).
  • the "lymphocyte ratio” indicates the number of lymphocytes to the number of white blood cells as a percentage.
  • Neutrophil ratio and lymphocyte ratio are included in the endpoints of conventional blood tests and can be obtained by conventional methods, for example, using an automatic blood cell analyzer or by visual examination, ELISA, flow cytometry or flow cytometry. Can be done. Counting of white blood cells, neutrophils and lymphocytes and calculation of neutrophil ratio and lymphocyte ratio may be performed by any method well known to those skilled in the art.
  • the neutrophil ratio and lymphocyte ratio can be measured using markers of neutrophils and lymphocytes, respectively.
  • Neutrophil markers are, for example, CD14, CD32, CD64, CD11b, CD16, CD18, CD44, CD55 and the like.
  • Lymphocyte markers include, for example, CD3 (T cells), CD19 (B cells), CD20 (B cells), CD56 (NK cells), CD7 (T cells, NK cells) and the like.
  • the neutrophil ratio and the lymphocyte ratio can be measured using reagents that stain neutrophils and lymphocytes, respectively.
  • the neutrophil staining reagent is, for example, Maygrunwald stain plus Gimza stain (Maygimza stain).
  • the lymphocyte staining reagent is, for example, Wright's stain plus Gimza stain (Wright's Gimza stain).
  • a patient's neutrophil or lymphocyte ratio and a preset neutrophil or lymphocyte ratio threshold are used to determine if the patient is eligible for peptide vaccine therapy. Compare with. For example, if a patient's neutrophil ratio is lower than the neutrophil ratio threshold and / or if the patient's lymphocyte ratio is higher than the lymphocyte ratio threshold, the patient is eligible for peptide vaccine therapy. Can be determined to be. For example, if a patient's neutrophil ratio is below the neutrophil ratio threshold and / or if the patient's lymphocyte ratio is above the lymphocyte ratio threshold, the patient is eligible for peptide vaccine therapy. Can be determined to be.
  • the threshold value can be set by a known method using various statistical analysis methods. In general, for the patient group (active drug group) to which the peptide vaccine was administered, the neutrophil ratio or lymphocyte ratio of the group showing the therapeutic effect (response group) and the group in which the therapeutic effect was not confirmed.
  • a threshold can be set by statistically processing the neutrophil ratio or lymphocyte ratio of the (non-responder group). Multiple thresholds can be set for each of the neutrophil ratio or the lymphocyte ratio. Thresholds can also be set for patient groups subgrouped according to characteristics. For example, thresholds may be set according to the type, sex, age group, or race of the cancer. Statistical analysis software such as SAS Ver. 9.4 can be used to set the threshold value.
  • the neutrophil ratio or lymphocyte ratio threshold is a value that allows the active group to be divided into a response group and a non-response group with a statistically significant difference.
  • the statistically significant difference may be analyzed by a known assay method. Without limitation, such a test method may be a log rank test.
  • the threshold can be set based on sensitivity and / or specificity. Preferably, the threshold indicates both high sensitivity and high specificity.
  • sensitivity means a true positive rate.
  • Specificity means a true negative rate.
  • a neutrophil ratio or a lymphocyte ratio that shows a high positive rate in the response group and a high negative rate in the non-response group can be set as a threshold value.
  • the threshold value can be set by ROC analysis (receiver operating characteristic analysis), which is generally used as a method for examining the usefulness of a diagnostic test.
  • ROC analysis receiver operating characteristic analysis
  • an ROC curve is created in which the sensitivity at each threshold value is plotted on the vertical axis and the false positive rate (1-specificity) is plotted on the horizontal axis.
  • the ROC curve becomes a straight line on a diagonal line in a test without diagnostic ability, but as the diagnostic ability improves, it becomes a curve that draws an arc to the upper left. It can be said that the threshold value that gives a point on the ROC curve that minimizes the distance to the upper left corner is excellent in sensitivity and specificity. It is also possible to set a threshold value based on the Youden index.
  • the sensitivity and specificity are obtained from the neutrophil ratio or lymphocyte ratio of the response group and the non-response group, and based on these values, a ROC curve is created using commercially available analysis software. Then, a value when the sensitivity and specificity are as close to 100% as possible can be obtained, and that value can be used as a threshold value.
  • the total number of cases of diagnostic efficiency (that is, cases in which a patient whose treatment was effective was correctly diagnosed as "effective” and a patient whose treatment was ineffective was correctly diagnosed as "ineffective”.
  • the ratio to the number can be obtained, and the neutrophil ratio or lymphocyte ratio at which the highest diagnostic efficiency is calculated can be used as the threshold.
  • the threshold for the neutrophil ratio is, for example, in the range of about 55% to 75%, about 60% to 70%, or about 63% to 65%, for example, about 64%.
  • the lymphocyte ratio threshold is, for example, in the range of about 15% to 35%, about 20% to 30% or about 25% to 27%, for example about 26%.
  • the threshold value is not limited to these values, and can be appropriately set according to factors such as the purpose of diagnosis, the characteristics of the patient, the type of disease, and the type of peptide vaccine agent.
  • therapeutic effect is not limited to "qualified person” and “not qualified person”.
  • qualified person may be expressed as “high possibility of response”, “responsiveness to treatment”, “expected therapeutic effect”, etc.
  • not qualified person may be expressed as "possibility of response”. It may be expressed as “low”, “not responsive to treatment”, “cannot expect therapeutic effect”, and the like.
  • Therapeutic effect is, for example, prolongation of overall or progression-free survival, eg, prolongation of overall or progression-free survival compared to median overall or progression-free survival in the placebo or untreated group. It may be.
  • the present disclosure provides a kit for determining whether a cancer patient is eligible for peptide vaccine therapy, including reagents for measuring neutrophil ratio and / or lymphocyte ratio.
  • the kit is an automated blood cell analyzer, visual examination, ELISA, flow cytometry or a kit for flow metric measurements.
  • Measuring reagents include, but are not limited to, reagents that specifically bind to neutrophil markers and / or lymphocyte markers, such as antibodies.
  • the kit can be appropriately manufactured by a conventional method.
  • a method of determining whether a cancer patient is eligible for peptide vaccine therapy (1) Collecting blood from the patient 7 to 35 days before the scheduled administration date of the peptide vaccine. (2) Measuring the neutrophil ratio and / or lymphocyte ratio of the blood, and (3) Determining whether the patient is eligible for peptide vaccine therapy based on the measured neutrophil ratio and / or lymphocyte ratio. Methods are provided that include.
  • reagents for measuring neutrophil ratio and / or lymphocyte ratio are provided that are used in a method of determining whether a cancer patient is eligible for peptide vaccine therapy.
  • the use of reagents for measuring neutrophil ratio and / or lymphocyte ratio is provided in a method for determining whether a cancer patient is eligible for peptide vaccine therapy.
  • the use of reagents for measuring neutrophil ratio and / or lymphocyte ratio is provided to produce a diagnostic agent for determining whether a cancer patient is eligible for peptide vaccine therapy.
  • treatment of cancer comprises administering to a patient determined to be eligible for peptide vaccine therapy by the determination method described above, a peptide vaccine containing an effective amount of at least one peptide antigen.
  • a method is provided. The features related to the peptide antigen, the peptide vaccine, the determination step, the cancer, the patient, the administration method, the threshold value, etc. described in the present disclosure regarding the determination method are also applied to the invention relating to the treatment.
  • “treatment” means reducing or eliminating the cause of cancer, delaying or stopping the progression, recurrence or metastasis of cancer, and / or reducing the symptoms of cancer in cancer patients. Means mitigation, improvement or elimination.
  • the present disclosure is a method of treating a patient suffering from cancer, the step of determining whether or not the patient is eligible for peptide vaccine therapy by the determination method described above; and based on the determination.
  • a treatment method comprising the step of administering to a patient a peptide vaccine agent containing an effective amount of at least one peptide antigen.
  • it is a method of treating cancer.
  • (1) Collecting blood from the patient 7 to 35 days before the scheduled administration date of the peptide vaccine.
  • (2) Measuring the neutrophil ratio and / or lymphocyte ratio of the blood, and (3) Determining whether the patient is eligible for peptide vaccine therapy based on the measured neutrophil ratio and / or lymphocyte ratio, and (4)
  • Methods are provided that include.
  • the present disclosure provides a peptide vaccine comprising at least one peptide antigen for treating cancer in a patient who has been determined to be eligible for peptide vaccine therapy by the above determination method.
  • the peptide vaccine agent may be the above-mentioned tailor-made peptide vaccine agent or non-tailor-made peptide vaccine agent.
  • a method of treating cancer comprises administering a peptide antigen to a patient determined by the determination methods of the present disclosure to be eligible for peptide vaccine therapy.
  • a peptide antigen is provided for treating cancer in a patient who has been determined to be eligible for peptide vaccine therapy by the determination methods of the present disclosure.
  • the use of peptide antigens is provided in the treatment of cancer in patients who are qualified for peptide vaccine therapy by the determination methods of the present disclosure.
  • the use of a peptide antigen is provided to produce a peptide vaccine for treating cancer in a patient who has been determined to be eligible for peptide vaccine therapy by the determination methods of the present disclosure.
  • the present disclosure provides a treatment kit for preparing tailor-made peptide vaccines.
  • the treatment kit comprises at least one peptide antigen selected from the 31 peptide antigens shown in Table 1, eg, at least one of them, preferably at least two, at least three, at least four, or maximum.
  • Tailor-made peptide vaccines can be prepared by selecting four peptide antigens.
  • the tailor-made peptide vaccine prepared by the treatment kit is administered to a patient who is determined to be qualified by the determination method according to the present invention.
  • the treatment kit contains at least one peptide antigen in powder or liquid form.
  • the treatment kit may further include, but is not limited to, a pharmaceutically acceptable carrier and an adjuvant to enhance the specific immune response induced by the peptide antigen.
  • the treatment kit can be appropriately manufactured by a conventional method. The characteristics related to the peptide vaccine agent, the adjuvant, and the like described in the above-mentioned determination method in the present disclosure are also applied to the treatment kit.
  • the peptide antigens used in tailor-made peptide vaccines are WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-109, Lck-208, PAP-213, Lck. Selection from the nine peptide antigens of -486 and Lck-90 provides a non-inferiority effect as compared to selection from the 31 peptide antigens shown in Table 1. A small number of candidate peptide antigens is preferred, for example, in terms of cost and ease of handling. Therefore, the present disclosure provides a kit containing these nine peptide antigens. This kit can be used to prepare tailor-made peptide vaccines for treating cancer. The features of the tailor-made peptide vaccines and kits described with respect to the determination methods described above in the present disclosure also apply to this kit.
  • the present disclosure is a kit comprising one or more polynucleotides, the one or more polynucleotides comprising WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-.
  • a kit is provided in which 109, Lck-208, PAP-213, Lck-486 and Lck-90 are encoded. This kit can be used to prepare tailor-made peptide vaccines for treating cancer.
  • the polynucleotide may be in the form of any nucleic acid, such as DNA or RNA. These polynucleotides can be easily produced based on the amino acid sequence information of the peptide and the sequence information of the DNA encoding the peptide. Specifically, it can be produced by ordinary DNA synthesis, amplification by PCR, or the like.
  • the kit comprises one or more polynucleotides, each polynucleotide may encode one or more peptide antigens.
  • the present disclosure is a kit comprising one or more expression vectors, wherein the one or more expression vectors allow WHSC2-103, CypB-129, UBE-43, HNRPL-140, A kit is provided in which SART3-109, Lck-208, PAP-213, Lck-486 and Lck-90 are encoded.
  • This kit can be used to prepare tailor-made peptide vaccines for treating cancer.
  • the kit comprises one or more vectors, each vector which may encode one or more peptide antigens.
  • the expression vector used here can be appropriately selected depending on the host to be used, the purpose, etc., and examples thereof include plasmids, phage vectors, and viral vectors.
  • examples of the vector include plasmid vectors such as pUC118, pUC119, pBR322 and pCR3, and phage vectors such as ⁇ ZAPII and ⁇ gt11.
  • examples of the vector include pYES2 and pYEura3.
  • the host is an insect cell, pAcSGHisNT-A and the like can be mentioned.
  • plasmid vectors such as pKCR, pCDM8, pGL2, pcDNA3.1, pRc / RSV, pRc / CMV, and viral vectors such as retrovirus vector, adenovirus vector, and adeno-related virus vector can be mentioned. Be done.
  • the vector may appropriately have factors such as a promoter capable of inducing expression, a gene encoding a signal sequence, a marker gene for selection, and a terminator.
  • a sequence that brings about a fusion protein with thioredoxin, His tag, GST (glutathione S-transferase), etc. may be added so as to facilitate isolation and purification.
  • a GST fusion protein vector such as pGEX4T having an appropriate promoter (lac, tac, trc, trp, CMV, SV40 early promoter, etc.) that functions in the host cell, or a vector having a tag sequence such as Myc, His, etc. (PDNA3.1 / Myc-His, etc.), and a vector (pET32a) expressing a fusion protein with thioredoxin and His tag can be used.
  • transformed cells containing the expression vector can be prepared.
  • the host used here include Escherichia coli, yeast, insect cells, animal cells and the like.
  • E. coli include HB101 strain, C600 strain, JM109 strain, DH5 ⁇ strain, AD494 (DE3) strain of E. coli K-12 strain.
  • yeast include Saccharomyces cervigier and the like.
  • animal cells include L929 cells, BALB / c3T3 cells, C127 cells, CHO cells, COS cells, Vero cells, HeLa cells and the like.
  • insect cells include sf9.
  • a usual introduction method suitable for the host cell may be used. Specific examples thereof include a calcium phosphate method, a DEAE-dextran method, an electroporation method, and a method using a gene transfer lipid (Lipofectamine, Lipofectin; Gibco-BRL).
  • a gene transfer lipid Lipofectamine, Lipofectin; Gibco-BRL.
  • a method for determining whether or not a cancer patient is eligible for peptide vaccine therapy which was collected from a cancer patient approximately 7 to 35 days before the scheduled administration date of the peptide vaccine.
  • a method comprising determining whether a patient is eligible for peptide vaccine therapy based on blood neutrophil ratio and / or lymphocyte ratio.
  • [A-3] The method according to paragraph A-2, wherein when the neutrophil ratio of a patient is less than the threshold value of the neutrophil ratio, the patient is determined to be eligible for peptide vaccine therapy.
  • [A-4] The method according to paragraph A-3, wherein the neutrophil ratio threshold is in the range of about 55% to 75%.
  • [A-5] The method according to paragraph A-3 or A-4, wherein the neutrophil ratio threshold is in the range of about 60% to 70%.
  • [A-6] The method according to any one of Items A-3 to A-5, wherein the neutrophil ratio threshold is in the range of about 63% to 65%.
  • [A-7] The method according to any one of Items A-3 to A-6, wherein the threshold value of the neutrophil ratio is about 64%.
  • [A-15] The method according to any one of Items A-1 to A-14, wherein the blood is collected about 7 to 21 days before the scheduled administration date of the peptide vaccine.
  • [A-16] The method according to any one of Items A-1 to A-15, wherein the blood is collected about 11 to 17 days before the scheduled administration date of the peptide vaccine.
  • [A-17] The method according to any one of Items A-1 to A-16, wherein the blood is collected about 13 to 15 days before the scheduled administration date of the peptide vaccine.
  • [A-18] The method according to any one of Items A-1 to A-14, wherein the blood is collected about 14 to 28 days before the scheduled administration date of the peptide vaccine.
  • peptide vaccine therapy is a tailor-made peptide vaccine therapy.
  • Tailor-made peptide vaccine therapy includes CypB-129, Lck-246, Lck-422, MAP-432, WHSC2-103, HNRPL-501, UBE-43, UBE-85, WHSC2-141, HNRPL- 140, SART3-302, SART3-309, SART2-93, SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3-1293, SART2-161, Lck-486, From the group consisting of Lck-488, PSMA-624, EZH2-735, PTHrP-102, SART3-511, SART3-734, Lck-90, Lck-449 and PAP-248 to the patient's immune responsiveness to each peptide antigen.
  • peptide vaccine agent comprises at least one peptide antigen selected based on it.
  • Tailor-made peptide vaccine therapy includes SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-1293, Lck-486, Lck-488, PSMA-624, PTHrP- For each peptide antigen from the group consisting of 102, CypB-129, Lck-246, WHSC2-103, UBE-43, WHSC2-141, HNRPL-140, SART3-302, SART3-734, Lck-90 and Lck-449.
  • peptide vaccine agent comprises at least one peptide antigen selected based on the patient's immune reactivity.
  • Tailor-made peptide vaccine therapy includes SART2-93, SART3-109, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3-1293, SART2-161, Lck-486, Lck- A-22.
  • the patient is HLA-A24 positive and tailor-made peptide vaccine therapy is SART2-93, SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3. At least one selected from the group consisting of -1293, SART2-161, Lck-486, Lck-488, PSMA-624, EZH2-735, PTHrP-102 based on the patient's immunoreactivity to each peptide antigen.
  • the patient is HLA-A2-positive and tailor-made peptide vaccine therapy is CypB-129, Lck-246, Lck-422, MAP-432, WHSC2-103, HNRPL-501, UBE-43, UBE.
  • the patient is HLA-A3, HLA-A11, HLA-A31 or HLA-A33 positive, and tailor-made peptide vaccine therapy is CypB-129, Lck-422, WHSC2-103, SART3-109, SART3.
  • the method according to any one of paragraphs A-22 or A-23.
  • the patient is HLA-A26 positive and the tailor-made peptide vaccine therapy is from the group consisting of MAP-432, WHSC2-103, HNRPL-501 and SART3-109, and the patient's immunoreactivity to each peptide antigen.
  • A-22 or A-23 wherein the peptide vaccine agent comprises at least one peptide antigen selected based on.
  • the peptide vaccine agent comprises at least two peptide antigens.
  • the peptide vaccine agent contains up to four types of peptide antigens.
  • the peptide antigens are selected in descending order of immunoreactivity of the patient.
  • Non-tailor-made peptide vaccine therapies include CypB-129, Lck-246, Lck-422, MAP-432, WHSC2-103, HNRPL-501, UBE-43, UBE-85, WHSC2-141, HNRPL.
  • Non-tailor-made peptide vaccine therapy includes SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-1293, Lck-486, Lck-488, PSMA-624, PTHrP. At least selected from the group consisting of -102, CypB-129, Lck-246, WHSC2-103, UBE-43, WHSC2-141, HNRPL-140, SART3-302, SART3-734, Lck-90 and Lck-449.
  • Non-tailor-made peptide vaccine therapy includes SART2-93, SART3-109, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3-1293, SART2-161, Lck-486, Lck. 4. 88, wherein the peptide vaccine agent comprises at least one peptide antigen selected from the group consisting of PSMA-624 and PTHrP-102, according to any of paragraphs A-33 to A-35. Method.
  • Patients are HLA-A24 positive and non-tailor-made peptide vaccine therapies include SART2-93, SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-503, It is due to a peptide vaccine containing at least one peptide antigen selected from the group consisting of MRP3-1293, SART2-161, Lck-486, Lck-488, PSMA-624, EZH2-735, PTHrP-102.
  • HLA-A2-positive and non-tailor-made peptide vaccine therapies include CypB-129, Lck-246, Lck-422, MAP-432, WHSC2-103, HNRPL-501, UBE-43, A-33 or A, which is a peptide vaccine containing at least one peptide antigen selected from the group consisting of UBE-85, WHSC2-141, HNRPL-140, SART3-302 and SART3-309. The method according to paragraph 34.
  • Patients are HLA-A3, HLA-A11, HLA-A31 or HLA-A33 positive, and non-tailor-made peptide vaccine therapies include CypB-129, Lck-422, WHSC2-103, SART3-109, A-33 or A, which comprises a peptide vaccine containing at least one peptide antigen selected from the group consisting of SART3-511, SART3-734, Lck-90, Lck-449 and PAP-248. The method according to paragraph 34.
  • Patients are HLA-A26 positive and non-tailor made peptide vaccine therapy is at least one peptide antigen selected from the group consisting of MAP-432, WHSC2-103, HNRPL-501 and SART3-109.
  • Cancers are prostate cancer, lung cancer, breast cancer, colon cancer, stomach cancer, hepatocellular carcinoma, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer, The method according to any one of Items A-1 to A-41.
  • the cancer is prostate cancer, lung cancer, breast cancer, colon cancer, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer, items A-1 to 1.
  • A-44 The method according to any of paragraphs A-1 to A-43, wherein the cancer is prostate cancer.
  • [A-45] The method according to any of paragraphs A-1 to A-44, wherein the cancer is castration-resistant prostate cancer.
  • [A-46] The method according to any of paragraphs A-1 to A-45, wherein the cancer is metastatic castration-resistant prostate cancer.
  • [A-47] The method according to any of paragraphs A-1 to A-46, wherein the cancer is docetaxel non-responsive prostate cancer.
  • [A-48] The cancer is prostate cancer, lung cancer, breast cancer, colon cancer, stomach cancer, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer, and the judgment is neutrophil.
  • Cancer is prostate cancer, lung cancer, breast cancer, colon cancer, hepatocellular carcinoma, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer.
  • Cancer is prostate cancer, lung cancer, breast cancer, colon cancer, hepatocellular carcinoma, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer.
  • the method according to any one of Items A-1 to A-42 which is carried out based on the neutrophil ratio and the lymphocyte ratio.
  • [A-51] The method according to any one of Items A-1 to A-50, which comprises measuring the neutrophil ratio and / or the lymphocyte ratio of blood collected from a cancer patient.
  • a kit for determining whether a cancer patient is eligible for peptide vaccine therapy which comprises a reagent for measuring neutrophil ratio and / or lymphocyte ratio.
  • A-53 The kit according to paragraph A-52, which is used for the method according to any one of paragraphs A-1 to A-51.
  • [A-54] The kit according to paragraph A-52 or A-53, wherein the reagent is an antibody that specifically binds to a neutrophil marker and / or a lymphocyte marker.
  • the peptide vaccine according to paragraph A-55 which is the peptide vaccine agent according to any one of paragraphs A-23 to A-32 and A-34 to A-41.
  • Agent. [A-57] Prepare a peptide vaccine agent for treating cancer in a patient determined to be eligible for peptide vaccine therapy by the method according to any one of paragraphs A-1 to A-51.
  • SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-1293, Lck-486, Lck-488, PSMA-624, PTHrP-102, CypB-129, Lck Includes at least one peptide antigen selected from the group consisting of -246, WHSC2-103, UBE-43, WHSC2-141, HNRPL-140, SART3-302, SART3-734, Lck-90 and Lck-449.
  • kits according to any one of Items A-57 to A-59 which comprises at least one peptide antigen selected from the group consisting of -102.
  • the kit according to any one of Items A-57 to A-60 which comprises two or more kinds of peptide antigens.
  • the peptide vaccine is intended to be administered to patients who are positive for HLA-A24, HLA-A2, HLA-A3, HLA-A11, HLA-A31, HLA-A33 or HLA-A26.
  • A-64 The peptide vaccine agent according to any one of A-55 to A-63, wherein the cancer is one according to any of A-42 to A-47. Or a kit.
  • Cancers are prostate cancer, lung cancer, breast cancer, colon cancer, stomach cancer, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer, and peptide vaccines are available.
  • Cancers are prostate cancer, lung cancer, breast cancer, colon cancer, hepatocellular carcinoma, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer, peptide vaccine
  • the peptide vaccine according to any one of paragraphs A-55 to A-64, wherein the agent is to be administered to a patient who is determined to be eligible for peptide vaccine therapy based on the lymphocyte ratio. Agent or kit.
  • Cancers are prostate cancer, lung cancer, breast cancer, colon cancer, hepatocellular carcinoma, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer or ovarian cancer, peptide vaccine Any of paragraphs A-55 to A-64, wherein the agent is to be administered to a patient who is determined to be eligible for peptide vaccine therapy based on neutrophil ratio and lymphocyte ratio.
  • [B-1] A method for determining whether or not a cancer patient is eligible for tailor-made peptide vaccine therapy.
  • the cancer patient is about 7 to 35 days before the scheduled administration date of the tailor-made peptide vaccine.
  • a method comprising determining whether a patient is eligible for tailor-made peptide vaccine therapy based on the neutrophil ratio and / or lymphocyte ratio of blood collected from.
  • the method according to paragraph B-1 which comprises measuring the neutrophil ratio and / or the lymphocyte ratio of blood collected from a cancer patient.
  • a patient is eligible for tailor-made peptide vaccine therapy by comparing the patient's neutrophil ratio and / or lymphocyte ratio to the neutrophil ratio and / or lymphocyte ratio threshold. The method according to paragraph B-1 or B-2, which determines whether or not.
  • [B-4] The method according to paragraph B-3, wherein when the neutrophil ratio of a patient is less than the threshold value of the neutrophil ratio, the patient is determined to be eligible for tailor-made peptide vaccine therapy. ..
  • [B-5] The method according to paragraph B-4, wherein the neutrophil ratio threshold is in the range of about 55% to 75%.
  • [B-6] The method according to paragraph B-4 or B-5, wherein the neutrophil ratio threshold is in the range of about 60% to 70%.
  • [B-7] The method according to any one of Items B-4 to B-6, wherein the neutrophil ratio threshold is in the range of about 63% to 65%.
  • [B-8] The method according to any one of Items B-4 to B-7, wherein the threshold value of the neutrophil ratio is about 64%.
  • the neutrophil ratio threshold is in the range of about 55% to 75% and the lymphocyte ratio threshold is in the range of about 15% to 35%.
  • Clause B-14 or B-15 where the neutrophil ratio threshold is in the range of about 60% to 70% and the lymphocyte ratio threshold is in the range of about 20% to 30%. The method described in the section.
  • Tailor-made peptide vaccine therapy includes CypB-129, Lck-246, Lck-422, MAP-432, WHSC2-103, HNRPL-501, UBE-43, UBE-85, WHSC2-141, HNRPL- 140, SART3-302, SART3-309, SART2-93, SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3-1293, SART2-161, Lck-486, From the group consisting of Lck-488, PSMA-624, EZH2-735, PTHrP-102, SART3-511, SART3-734, Lck-90, Lck-449 and PAP-248 to the patient's immune responsiveness to each peptide antigen.
  • the patient is HLA-A24 positive and tailor-made peptide vaccine therapy is SART2-93, SART3-109, Lck-208, PAP-213, PSA-248, EGFR-800, MRP3-503, MRP3. At least one selected from the group consisting of -1293, SART2-161, Lck-486, Lck-488, PSMA-624, EZH2-735, PTHrP-102 based on the patient's immunoreactivity to each peptide antigen.
  • the method according to any one of Items B-1 to B-23, which is based on a tailor-made peptide vaccine agent containing a peptide antigen.
  • the patient is HLA-A24 positive and the tailor-made peptide vaccine therapy is from the group consisting of SART3-109, Lck-208, PAP-213 and Lck-486, the patient's immunoreactivity to each peptide antigen.
  • the method according to any one of Items B-1 to B-23, which is based on a tailor-made peptide vaccine agent containing at least one peptide antigen selected based on the above.
  • the patient is HLA-A2-positive and tailor-made peptide vaccine therapy is CypB-129, Lck-246, Lck-422, MAP-432, WHSC2-103, HNRPL-501, UBE-43, UBE.
  • the method according to any one of Items B-1 to B-23, which is based on an agent.
  • the patient is HLA-A2-positive and the tailor-made peptide vaccine therapy consists of the group consisting of WHSC2-103, CypB-129, UBE-43 and HNRPL-140, and the patient's immunoreactivity to each peptide antigen.
  • the method according to any one of Items B-1 to B-23, which is based on a tailor-made peptide vaccine agent containing at least one peptide antigen selected based on the above.
  • the patient is HLA-A3, HLA-A11, HLA-A31 or HLA-A33 positive, and tailor-made peptide vaccine therapy is CypB-129, Lck-422, WHSC2-103, SART3-109, SART3.
  • the method according to any one of Items B-1 to B-23, which is based on an agent.
  • the patient is HLA-A3, HLA-A11, HLA-A31 or HLA-A33 positive and the tailor-made peptide vaccine therapy consists of WHSC2-103, CypB-129, SART3-109 and Lck-90.
  • the patient is HLA-A26 positive and the tailor-made peptide vaccine therapy is from the group consisting of MAP-432, WHSC2-103, HNRPL-501 and SART3-109, and the patient's immunoreactivity to each peptide antigen.
  • Patients are HLA-A26 positive and tailor-made peptide vaccine therapy was selected from the group consisting of WHSC2-103 and SART3-109 based on the patient's immunoreactivity to each peptide antigen.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, and head and neck.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, and head and neck.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, head and neck cancer, sarcoma, and esophageal cancer.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, head and neck cancer, sarcoma, and esophageal cancer.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, and head and neck.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, and head and neck.
  • kits for determining whether a cancer patient is eligible for tailor-made peptide vaccine therapy which comprises a reagent for measuring neutrophil ratio and / or lymphocyte ratio.
  • a reagent for measuring neutrophil ratio and / or lymphocyte ratio comprises a reagent for measuring neutrophil ratio and / or lymphocyte ratio.
  • the patient is tailor-made.
  • the tailor-made peptide vaccine is a blood collected from a cancer patient about 7 to 35 days before the scheduled administration date of the tailor-made peptide vaccine.
  • a determination method that includes determining whether the patient is eligible for tailor-made peptide vaccine therapy based on the neutrophil ratio and / or lymphocyte ratio of A kit for treating cancer in patients who have been determined to be present.
  • a tailor-made peptide vaccine is intended to be administered to patients who are HLA-A24, HLA-A2, HLA-A3, HLA-A11, HLA-A31, HLA-A33 or HLA-A26 positive.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, head and neck cancer, sarcoma, and esophagus. It is intended to be administered to patients with cancer, kidney cancer or gastric cancer who are qualified for tailor-made peptide vaccine therapy based on the neutrophil ratio.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, and head and neck.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, and head and neck.
  • sarcoma, esophageal cancer or kidney cancer who are qualified for tailor-made peptide vaccine therapy based on neutrophil ratio and lymphocyte ratio.
  • kits containing one or more expression vectors for preparing a tailor-made peptide vaccine for treating cancer wherein the one or more expression vectors WHSC2-103. , CypB-129, UBE-43, HNRPL-140, SART3-109, Lck-208, PAP-213, Lck-486 and Lck-90, a kit.
  • B-64 Containing one or more transformed cells comprising one or more polynucleotides or one or more expression vectors for preparing tailor-made peptide vaccines for treating cancer.
  • Kit with the one or more polynucleotides or one or more expression vectors, WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-109, Lck-208, PAP-213. , Lck-486 and Lck-90 are coded, kit.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, and head and neck.
  • the kit according to any one of paragraphs B-61 to B-64, which is cancer, sarcoma, esophageal cancer, kidney cancer or gastric cancer.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, hepatocellular carcinoma, and head and neck.
  • Cancers include lung cancer, prostate cancer, colon cancer, pancreatic cancer, breast cancer, urinary tract cancer, biliary tract cancer, ovarian cancer, uterine cancer, head and neck cancer, sarcoma, and esophagus.
  • the kit according to any one of Items B-61 to B-64 which is cancer, kidney cancer or gastric cancer.
  • kits containing WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-109, Lck-208, PAP-213, Lck-486 and Lck-90 [B-69] A kit containing one or more polynucleotides, depending on the one or more polynucleotides, WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-109, Lck. A kit in which -208, PAP-213, Lck-486 and Lck-90 are encoded.
  • a kit containing one or more transformed cells comprising one or more polynucleotides or one or more expression vectors, said one or more polynucleotides or one or more.
  • WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-109, Lck-208, PAP-213, Lck-486 and Lck-90 are encoded by the expression vector of the kit.
  • HLA-A24-positive castration-resistant prostate cancer (CRPC) patients who had progressed within 12 months after docetaxel chemotherapy were enrolled in clinical trials from 68 medical facilities nationwide. Eligible patients were patients over the age of 20 with histologically confirmed prostate adenocarcinoma. Other selection criteria were as follows: Immunoglobulin G (IgG) positive reaction to 2 or more of the 12 candidate peptides shown in Table 2 at the time of screening test; Eastern Cooperative Oncology Group, USA Group (ECOG) performance status (PS) is 0 or 1; life expectancy is 12 weeks or more; serum testosterone concentration is 50 ng / dl or less; and sufficient bone marrow function, liver function, and renal function.
  • IgG Immunoglobulin G
  • Eligible patients were patients over the age of 20 with histologically confirmed prostate adenocarcinoma.
  • Other selection criteria were as follows: Immunoglobulin G (IgG) positive reaction to 2 or more of the 12 candidate peptides shown
  • Exclusion criteria included a history of acute infections, severe allergic reactions; lung, heart, or other systemic disorders; and other symptoms that were inappropriate for inclusion as judged by the clinician. Past use of enzalutamide or avilateron was tolerated.
  • Treatment Patients receiving tailor-made peptide vaccine (PPV) or placebo using the following stratified factor minimization method were randomly assigned in a 2: 1 ratio: age (75) per participating institution.
  • the study was double-blind and all physicians, patients, and researchers who performed interventions, outcome assessments, and data analysis were unaware of the treatments assigned to them.
  • OS overall survival
  • PFS progression-free survival
  • PFS was defined as the time period from patient randomization to the detection of objective disease progression based on the PSA Working Group's Consensus Criteria 2, Solid Cancer Efficacy Criteria 1.1 or Death.
  • IgG antibody titer measured by Luminex system using blood samples collected before and every 6 treatments ( Komatsu N, Shichijo S, Nakagawa M, et al. Scand J Clin Lab Invest 2004; 64: 535-45) And cytotoxic T lymphocyte (CTL) activity (Hida N, Maeda Y, Katagiri K, et al. Cancer Immunol Immunother 2002; 51: 219-28) measured by interferon gamma (IFN- ⁇ ) release assay. Based on this, the patient's immune response was evaluated. Safety was assessed based on physical examination, vital sign measurements, laboratory analysis, and adverse events (AEs) graded using Common Terminology Criteria for Adverse Events version 4.0. ..
  • FAS efficacy analyzes were based on the largest population to be analyzed (FAS).
  • FAS is defined as a patient who has undergone at least one treatment.
  • HR hazard ratio
  • follow-up was completed in October 2017 and final analysis was performed on the database frozen in May 2018.
  • the survival curve was drawn by the Kaplan-Meier method, and the 95% confidence interval (CI) was calculated.
  • the comparison of OS values was performed by the Harriston-Fleming test. OSs in the PPV and placebo groups were compared using a stratified log-rank test based on randomized factors. The effect of treatment is reported as HR at 95% CI, and the p-values of subgroup category interactions are shown in forest plots.
  • the mean change in immune response from baseline at each time point was compared between the two groups in a linear regression model. All toxicity grades and severe (grade 3 or higher) toxicity were compared between the two groups (Fisher's exact test). All the results of the statistical test with a p value of less than 5% were found to be significant. All analyzes were performed with JMP version 13 software (SAS Institute, Cary, NC).
  • FIG. 1 shows a flow chart of a patient. There was no imbalance between the two randomized groups, except for low prostate-specific antigen (PSA) levels in the PPV group (Table 3).
  • PSA prostate-specific antigen
  • the median 1-year survival rates were similar between the PPV and placebo groups, at 62.3% and 62.4%.
  • Table 5 shows the detailed results of the correlation between the types of circulating leukocytes and the OS of the PPV group and placebo group.
  • the median OS of patients in the PPV group with a neutrophil ratio greater than or equal to the median ( ⁇ 70%) was significantly shorter than the median OS of patients in the PPV group with a low neutrophil ratio (HR1. 71, 95% CI: 1.3-2.3, p ⁇ 0.01).
  • the median OS of patients in the PPV group with a lymphocyte ratio above the median ( ⁇ 21.7%) was significantly longer than the median OS of patients in the PPV group with a low lymphocyte ratio ( ⁇ 21.7%).
  • the cutoff level of the most appropriate neutrophil ratio or lymphocyte ratio was analyzed.
  • the p-value of the interaction with a neutrophil ratio of 50% to 80%, the p-value of the interaction with a lymphocyte ratio of 10% to 40%, and the number of target patients at each point were plotted.
  • Analysis of the relationship between the p-value of the interaction of neutrophil ratio (Fig. 3A) and lymphocyte ratio (Fig. 3B) and the number of patients shows that the most appropriate neutrophil ratio and lymphocyte ratio cutoff. Levels were 64% and 26%, respectively (interaction p-value ⁇ 0.01 and more patients).
  • no significant difference was detected between the groups at any cutoff level in the neutrophil ratio and lymphocyte ratio of circulating blood (blood collected 1 to 2 hours before treatment) on the vaccine start date (Fig. 4). ..
  • PBMC peripheral blood mononuclear cell
  • the protocol has been approved by the institutional review or ethics committee of all participating institutions and has been registered in the UMIN clinical trial registry (UMIN 1482, 1839, 1844, 1847, 1850, 1854, 1855, 1856, 1875, 1881, 1882, 1883, 1884, 2228, 3590, 5632, 6249, 6295, 6493, 7493, 8126, 8823, 8824, 8825, 8826, 8827, 8828, 10068, 19390, 2906, 2907, 2908, 2988, 2985, 2987, 3027, 3028, 3029, 3059, 3060, 3081, 3082, 3083, 5329, 10290, 11593, 14855, 1882, 1879, 6927, 11230). All patients submitted written informed consent after being briefed on the entire protocol prior to study participation. This trial was conducted according to the principles of the Declaration of Helsinki.
  • Eligible patients are those 18 years or older with histologically identified malignancies.
  • the registered institutions are 2588 cases registered in Japan from November 2008 to March 2017.
  • the breakdown is lung cancer 399, prostate cancer 354, colon cancer 344, pancreatic cancer 290, stomach cancer 200, breast cancer 183, urinary tract cancer 139, biliary tract cancer 126, ovarian cancer 118, uterine cancer 79, liver.
  • human leukocyte antigen type is HLA-A2, -A24 or -A3 supertype (A3sup) : A3, A11, A31 or A33), or HLA-A26 positive cases.
  • Other selection criteria were: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1; Life Expectancy 12 Weeks or More, Sufficient Bone Marrow Function, Liver Function, and Maintains renal function.
  • Exclusion criteria included a history of acute infections, severe allergic reactions; lung, heart, or other systemic disorders; and other symptoms that were inappropriate for inclusion as judged by the clinician.
  • the safety and immunological effects of these 31 candidate peptides have been confirmed by past clinical trials, and all peptides are prepared by the Multiple Peptide System (San Diego, CA) under the conditions of good manufacturing practice. Was done.
  • HLA human leukocyte antigen
  • CypB cyclophyllin B
  • Lck p56lck
  • MAP microtubule binding protein
  • WHSC2 Wolf Hilsholn responsible region 2
  • HNRPL heteronuclear ribonucleoprotein L
  • UBE2V ubiquitin binding enzyme variant Kua SART3, squamous cell carcinoma antigen 3
  • SART2 squamous cell carcinoma antigen 2
  • PAP prostate acid phosphatase
  • PSA prostate-specific antigen
  • EGFR epithelial growth factor receptor
  • MRP3 multidrug resistance-related protein 3
  • PSMA Prostate-specific membrane antigen
  • EZH2 zeste homolog 2 enhancer
  • PTHrP parathyroid hormone-related peptide
  • the first cycle was set at 4 week intervals
  • the second cycle was set at 4 to 8 week intervals
  • the third and subsequent cycles were set at 4 to 12 week intervals.
  • the first dose was given 14 days after blood was drawn to determine the patient's eligibility for the trial. If it was difficult to go to the outpatient clinic due to cancer progression, the patient wished, or the attending physician judged that it was difficult to continue, the study was terminated.
  • OS overall survival
  • FAS efficacy analyzes were based on the largest population to be analyzed (FAS). FAS is defined as a patient who has undergone at least one treatment. The survival curve was drawn by the Kaplan-Meier method and a 95% confidence interval (CI) was calculated. All the results of the statistical test with a p value of less than 5% were found to be significant. All analyzes were performed with JMP version 13 software (SAS Institute, Cary, NC).
  • Result 1 A subgroup analysis was performed based on the neutrophil ratio in the circulating blood before participating in the clinical trial (at the time of registration). As a result, neutrophils at enrollment in prostate cancer, lung cancer, breast cancer, colon cancer, stomach cancer, urinary tract cancer, pancreatic cancer, biliary tract cancer, uterine cancer, ovarian cancer, and other cancers. When the ratio was compared between the two groups of less than 64% and 64% or more, the overall survival (median value) of each group of less than 64% was significantly longer than that of the group of cases of 64% or more. However, there was no significant difference in overall survival (median) between the two groups between brain tumor (glioblastoma) and hepatocellular carcinoma (liver cancer). Specific results are shown in the table below.
  • CRPC castration-resistant prostate cancer
  • Eligible patients were patients over the age of 20 with histologically confirmed prostate cancer.
  • Other selection criteria were as follows; Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1; Life Expectancy 12 Weeks or More; Serum Testosterone Concentration Less than 50 ng / dl; In addition, sufficient bone marrow function, liver function, and renal function.
  • Treatment of patients who had not previously undergone bilateral orchiectomy was continued with luteinizing hormone-releasing hormone agonists.
  • Exclusion criteria include a history of acute infections, severe allergic reactions; lung, heart, or other systemic disorders; and the development of other symptoms that are inappropriate for inclusion as judged by the clinician.
  • KRM20 non-tailor-made peptide vaccine
  • placebo placebo mixed with the 20 peptides listed in Treatment Table 11 were randomly assigned in a 1: 1 ratio.
  • Age under 65 years or over 65 years
  • PSA (20 ng / ml or less or over) were used as stratification factors for each participating facility. The study was double-blind and all physicians, patients, and researchers who performed interventions, outcome assessments, and data analysis were unaware of the treatments assigned to them.
  • the first dose was given 14 to 28 days after blood was drawn to determine the patient's eligibility for the trial.
  • On days 1-36 1 mg of dexamesadon was orally administered daily.
  • docetaxel 70 mg / m 2
  • Intravenous docetaxel and subcutaneous administration of the investigational drug were performed for 5 cycles at 3-week intervals. During that time, 1 mg of dexamesadon was orally administered every day.
  • A3 sup HLA-A3, A11, A31 or A33
  • OS overall survival
  • PFS progression-free survival
  • OS overall survival
  • FAS Statistical analysis All efficacy analyzes were based on the largest population to be analyzed (FAS). FAS is defined as a patient who has undergone at least one treatment. OS data was analyzed by the Kaplan-Meier method. The log rank test was used to compare the survival curves, and the Cox proportional hazard analysis was used to evaluate the hazard ratio (HR). The confidence interval (CI) was 95%. Statistical analysis was performed using SAS software version 9.1 (SAS Institute, Cary, NC) with a bilateral significance level of 5%.
  • Peptides were prepared by the Multiple Peptide System (San Diego, CA) or the American Peptide Company (Sunnyvale, CA) under good manufacturing practice conditions. The patient's existing immunity was determined by HLA type and peptide-specific IgG levels, and 2-4 peptides were selected accordingly. Each selected peptide was mixed with an incomplete Freund's adjuvant (Montanide ISA-51VG; Seppic, Paris, France) and injected subcutaneously into the groin, abdomen, neck, upper chest or upper back.
  • an incomplete Freund's adjuvant (Montanide ISA-51VG; Seppic, Paris, France) and injected subcutaneously into the groin, abdomen, neck, upper chest or upper back.
  • HLA human leukocyte antigen
  • CypB cyclophilin B
  • EGFR epithelial growth factor receptor
  • EZH2 zeste homolog 2 enhancer
  • HNRPL heteronuclear ribonucleoprotein L
  • Lck p56 lck
  • MAP microtubule binding protein
  • MRP3 Multidrug resistance related protein 3
  • PAP Prostate acid phosphatase
  • PSA Prostate specific antigen
  • PSMA Prostate specific membrane antigen
  • PTHrP Parathyroid hormone related peptide
  • SART2 Squamous epithelial cancer antigen 2
  • UBE2V Ubiquitin Binding Enzyme Variant Kua
  • WHSC2V Ubiquitin Binding Enzyme Variant Kua
  • WHSC2V Ubiquitin Binding Enzyme Variant Kua
  • WHSC2V Ubiquitin Binding Enzyme Variant Kua
  • Patients with PRT 1 or 2 received an emulsion of 1.5 mL (3 mg / each peptide) with each injection.
  • Patients with PRT3 received an emulsion of 3.0 mL (6 mg / each peptide) with each injection.
  • patients wishing to continue PPV after the second cycle were vaccinated at intervals of 2-12 weeks until withdrawal of consent or unacceptable toxicity. This trial was conducted in accordance with the principles of the Declaration of Helsinki and GCP guidelines.
  • the selection criteria were, as previously reported, a pathologically confirmed diagnosis of cancer; IgG-positive reactions to at least two of the 31 candidate peptides in pre-vaccinated plasma; HLA-A2, -A24. , -A3sup or -A26 positive; age ⁇ 20; US East Coast Cancer Clinical Trials Group (ECOG) Performance Status (PS) 0-2, and neurologically 3 for brain tumor patients; at least 12 weeks remaining life; Sufficient myeloid function, liver function, and renal function. Exclusion criteria were acute infections, a history of severe allergic reactions, or other systemic illnesses. All patients submitted written informed consent for study participation and data collection.
  • the mixture was washed with a versatile vacuum instrument and incubated with 100 ⁇ L of biotinylated goat anti-human IgG (Gamma chain specific; Vector Laboratories, Burlingame, CA) on a plate shaker at 25 ° C. for 1 hour.
  • the plates were washed, 100 ⁇ L of streptavidin-PE (Life Technologies) was added to each well and incubated on a plate shaker at 25 ° C. for 30 minutes.
  • the beads were washed 4 times, 100 ⁇ L of Tween-PBS was added to each well, and the Luminex system was used to detect the fluorescence intensity unit (FIU) of the beads.
  • the cutoff value for anti-peptide IgG was set to 10 FIU for 100-fold diluted samples.
  • OS was calculated as the number of months from the date of participation in the trial to the date of death or last contact.
  • the endpoints (Time-to-event endpoints) of the time until the event occurred were analyzed by the Kaplan-Meier method, and the comparison between OS groups was performed by the log rank test.
  • the clinical efficacy of individual peptides on OS was evaluated by univariate and multivariate analysis with a Cox proportional hazard regression model to calculate HR and 95% CI. All reported p-values were bilateral and p-values less than 0.05 were considered significant.
  • JMP version 12 or SAS version 9.4 software SAS Institute Inc., Cary, NC) was used for all analyses.
  • the median OS was 11.6 months (M) and 95% confidence interval (CI) 11.0-12.3 for all 2,588 patients.
  • the number of patients with each cancer was as follows: 399 lung cancers (11.9M, 95% CI: 10.0-13.5), 354 prostate cancers (11.9M, 95% CI: 10.0-13.5) 18.7, 16.1-22.3), colorectal cancer 344 (13.1, 11.3-15.5), pancreatic cancer 290 (5.7, 5.1-6.7)
  • gastric cancer (9.1, 7.6-10.4
  • 183 breast cancers (21.2, 15.6-28.4)
  • 818 other cancers Table 13).
  • the breakdown of these 818 cancer patients was 139 urinary tract cancer (9.9, 6.2-12.8), 126 biliary tract cancer (6.3, 5.1-8.0), and 118 ovarian cancers (18.0, 13.9-21.5), 79 uterine cancers (15.3, 10.0-21.4), 83 hepatocellular carcinomas (12.1, 10) .2-18.0), 50 head and neck cancers (10.6, 6.4-14.4), 49 sarcomas (10.3, 7.2-17.6), 39 esophageal cancers (7.5, 5.4-9.0), 35 brain tumors (12.3, 7.5-20.8), 30 kidney cancers (31.8, 10.4-59.8), There were 70 other rare cancers (data not disclosed).
  • the number of patients was 1,520 males and 1,068 females, and the median age was 63 years.
  • Median OS for men and women was 10.5 and 13.7M, respectively, and female patients with lung and colorectal cancer had longer OS than men.
  • Patients with better PS had longer OS for all types of cancer.
  • Patients in the earlier stages had longer OS than patients in the advanced stages of all cancers except colorectal cancer.
  • median OS was not significantly different due to HLA-class I differences (A24 + patients (1,550): 12.0M, A2 + patients (1,050): 11.5M, A3sup + patients (A3sup + patients). 1,214 patients): 11.1M, A26 + patients (552 patients): 12.4M) (Table 13).
  • the number of patients who received systemic treatment prior to PPV vaccination is as follows: surgery 1,574, targeting or chemotherapy 2,185, radiation. 771 cases of therapy or 220 cases of topical treatment.
  • the number of patients who received systemic treatment with PPV vaccination is as follows: surgery 74 patients, targeted or chemotherapy 1787 patients, radiation therapy 272 patients, or topical treatment 99 patients.
  • Systemic treatment before or during PPV by cancer type is also shown in Table 13.
  • the median number of vaccinations was 11 and was in the range of 1-76.
  • the median study period for all 2588 patients was 5.4M.
  • Table 13 shows each cancer.
  • the median follow-up was 11.3M.
  • Circulating blood cells and OS Table 14 shows the results of examining the correlation between the number or ratio of circulating blood cells before vaccination and OS.
  • Median OS in PPV patients with median neutrophil, monocyte or platelet counts above or below median is significantly shorter than median OS in PPV patients below it (p ⁇ 0.01), while lymphocytes
  • the median OS of PPV patients with a median number of red blood cells greater than or equal to the median was significantly longer than the median OS of PPV patients below it (p ⁇ 0.01).
  • HR was more sensitive than the number of cells.
  • Factors suitable or unsuitable for a more potent OS are median neutrophil ratio (64.8%, HR: 1.70) or median lymphocyte ratio (25.1%, HR: 0.53).
  • the coefficients (R 2 ) were 0.97 or 0.92, respectively (FIGS. 10 and 11).
  • the neutrophil ratio at registration was compared between the two groups of less than 64% and 64% or more. The results are shown in Table 15.
  • the lymphocyte ratio at enrollment was compared between the two groups of less than 26% and more than 26%. The results are shown in Table 16.
  • lymphocytes Lung cancer, colon cancer, prostate cancer, breast cancer, urinary tract cancer, pancreatic cancer, hepatocellular carcinoma, biliary tract cancer, uterine cancer, ovarian cancer, kidney cancer, esophageal cancer, head and neck cancer
  • median OS the median OS of patients with 26% or more lymphocytes was significantly longer than that of patients with less than 26%. There was no significant difference in median OS between the two groups for brain tumors, gastric cancer, and other cancers.
  • Table 17 lists peptides in descending order of positive rate. For example, SART2-93 and Lck-422 have positive rates of 87% (2,248 positive vs. 340 negative) and 12% (316 vs 2,272), respectively, listed in the top and bottom rows. In patients who showed detectable levels, the magnitude of IgG titers also varied among the 31 peptides, with a median FIU of 40 for each peptide, ranging from 23 to 111.
  • Post-vaccination IgG titers were measured at the end of the first cycle and at the end of the second cycle. Some patients (472 of 2,588, 18.3%) withdrew from clinical trials by the end of the first cycle due to the rapid progression of the disease. Of the 2,116 patients who completed at least the first cycle, the proportion of patients with a positive IgG response varied widely among the 31 peptides, ranging from 22-74% with a median of 48%. It was. EZH2-735 and Lck-422 induced positive immune responses at the highest and lowest rates, respectively (51 of 69 and 20 of 92, respectively) (Table 17). In patients who responded positively, the magnitude of IgG titers also varied significantly among the 31 peptides, with median FIUs for each peptide ranging from 312 to 25,121.
  • the level of correlation of each of the 31 peptides with OS is a Cox-proportional hazard. Evaluated with a regression model.
  • the median OS of patients vaccinated with the Lck-486, EGFR-800, PAP-213, HNRPL-140 or Lck-208 peptides was vaccinated without any of these. It was significantly longer than the patients who were vaccinated.
  • the median OS of vaccinated cases vs. non-vaccinated cases is 11.1 vs. 9.6M, 13.1 vs. 9.6, 14.9 vs.
  • HLA-A24, -A2 or -A3sup alleles are found in at least> 20% of the population worldwide, while HLA-A26 alleles are found in 11% of the Japanese population, 4% of the US Caucasian population, And it is found in 7.5% of the African population in Cape Town (Niu Y, et al., Cancer Sci 2009; 100: 2167-74). Therefore, four HLA-A24 compatible peptides, four HLA-A2 compatible peptides, four HLA-A3sup compatible peptides and two HLA-A26 compatible peptides were designed to be included in the new set.
  • peptide selection Details of peptide selection are shown in Tables 20 and 21 (selected peptides are shown in bold).
  • WHSC2-103, CypB-129, UBE-43 and HNRPL-140 peptides were selected as the four HLA-A2-compatible peptides.
  • SART3-109, Lck-208, PAP-213 and Lck-486 were selected as the four HLA-A24-compatible peptides.
  • WHSC2-103, CypB-129 and SART3-109 were selected as 3 of the 4 HLA-A3sup peptides.
  • PAP-248 was excluded because it had a shorter median OS than patients without it.
  • SART3-511 and SART3-734 were also excluded as SART3-109 derived from the common antigen had already been selected.
  • Lck-449 was also excluded due to the small number of patients. Therefore, Lck-90 was selected as the remaining one HLA-A3sup peptide. WHSC2-103 and SART3-109 were selected as the two HLA-A26 peptides. Vaccines of these new nine peptide sets (9P: WHSC2-103, CypB-129, UBE-43, HNRPL-140, SART3-109, Lck-208, PAP-213, Lck-486 and Lck-90) IgG levels or clinical correlations before and after vaccination were non-inferior to the remaining 22 peptide sets (22P) (bottom two rows of Tables 20 and 21).
  • At least one of these nine peptides was vaccinated in 2,274 (87.9%) of the 2,588 patients.
  • this set of 9 peptides is used as a candidate peptide for PPV in cancer patients (excluding gastric cancer and brain tumor) satisfying both neutrophil ⁇ 64% and lymphocyte ⁇ 26%, 31 peptides are used. It may show non-inferiority in terms of immune response and clinical utility as compared to the candidate peptide set. A small number of candidate peptides is preferable in terms of cost and ease of handling.
  • the eligibility of cancer patients for peptide vaccine therapy can be determined before the start of treatment. If the result is "ineligible,” the patient will have the opportunity to undergo other treatments and, from a health economic perspective, the cost of preparing or administering the peptide vaccine can be reduced. It brings the benefit of being able to. On the other hand, if the determination result is "qualified", the patient is provided with an opportunity to receive peptide vaccine therapy.
  • the present disclosure can also reduce the number of candidate peptide antigens in tailor-made peptide vaccine therapy.

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