CN113777323A - Application of IL-6 in non-small cell lung cancer immunotherapy - Google Patents

Abstract

The invention discloses an application of IL-6 in non-small cell lung cancer immunotherapy. The invention provides application of a substance for detecting the expression level of IL-6 in at least one of the following or preparing a product with at least one of the following functions: (1) predicting or assisting in predicting the efficacy of an immune monotherapy for treating non-small cell lung cancer; (2) predict or assist in predicting the length of progression-free survival after immune monotherapy treatment of non-small cell lung cancer. Experiments prove that IL-6 may have the potential of predicting the curative effect of the non-small cell lung cancer immune single drug therapy, and the anti-IL-6 antibody may enhance the anti-tumor effect of the immune therapy by relieving the immune suppression state of an organism.

Description

Application of IL-6 in non-small cell lung cancer immunotherapy

Technical Field

The invention belongs to the technical field of biology, and particularly relates to application of IL-6 in non-small cell lung cancer immunotherapy.

Background

To date, lung cancer is one of the highest causes of cancer-related deaths in china and even worldwide. With the rapid development of immunotherapy, the treatment pattern of advanced lung cancer changes day by day. The immune checkpoint pathway is a double-edged sword; it can maintain the immune homeostasis of normal body and help tumor cell to carry out immune escape. Programmed cell death protein 1 (PD-1)/programmed cell death ligand protein 1 (PD-L1) pathway can prevent CD8⁺T cells attack tumor cells, which in turn promote tumor proliferation or metastasis. Inhibitors directed against this pathway, i.e., anti-PD-1 or anti-PD-L1 antibodies, have now become the primary therapeutic drug of choice for a number of cancer species, including lung cancer, melanoma, renal cell carcinoma. Although the survival time of patients with advanced lung cancer after receiving immune single-drug therapy is obviously prolonged compared with chemotherapy, the disease remission rate of the patients is still not more than 20%. Most patients do not benefit from an immune monotherapy and some treated patients experience significant toxic reactions.

Therefore, it is necessary to find more accurate biomarkers with clinical transformation potential to guide the clinical application of the non-small cell lung cancer immune single drug therapy, not only to screen out the population benefiting from the immune single drug therapy and the drug-resistant population, but also to expand the response population of the immune therapy through multi-target combined therapy, and the biomarkers are important strategies for improving the effective rate of the immune therapy and realizing accurate medical treatment.

Disclosure of Invention

An object of the present invention is to provide the use of a substance for detecting the expression level of IL-6.

The invention provides an application of a substance for detecting the expression level of IL-6 in at least one of the following or preparing a product with at least one of the following functions:

(1) predicting or assisting in predicting the efficacy of an immune monotherapy for treating non-small cell lung cancer;

(2) predict or assist in predicting the length of progression-free survival of an immune monotherapy for non-small cell lung cancer.

In the application, the medicines adopted by the immune single-medicine treatment are PD-1 inhibitors and/or PD-L1 inhibitors.

In the application, the substance for detecting the expression quantity of the IL-6 is a substance for detecting the expression quantity of the IL-6 in the baseline plasma or the baseline tumor tissue of the patient with the non-small cell lung cancer to be detected;

alternatively, the substance for detecting the expression level of IL-6 in the baseline plasma or the baseline tumor tissue of the non-small cell lung cancer patient to be tested comprises an antibody or other molecule capable of specifically binding to IL-6.

The PD-1 inhibitor can be anti-PD-1 antibody, specifically nivolumetrizumab, Pabollizumab, Cedilizumab or Terepril monoclonal antibody.

The curative effect of the immune single medicine treatment is reflected in the survival rate without progress or the survival time without progress; at the same follow-up time, the progression-free survival rate of the test patients in the high expression group is less than or the candidates are less than that of the test patients in the low expression group.

The expression level of IL-6 in the tumor tissue was indicated by a staining score.

In the embodiment of the present invention, the substance for detecting the expression level of IL-6 in the baseline plasma or the baseline tumor tissue of the patient to be tested for non-small cell lung cancer is specifically a reagent for detecting the IL-6 level in peripheral blood by ELISA (including IL-6 antibody) or a reagent for detecting the IL-6 level in tumor tissue by immunohistochemistry (including IL-6 antibody).

The application of IL-6 as a marker in the development, screening and/or preparation of an agent for predicting or assisting in predicting the effect of the immune single drug therapy of the non-small cell lung cancer patient is also the protection scope of the invention.

It is another object of the invention to provide the use of anti-IL-6 antibodies.

The invention provides an anti-IL-6 antibody, which is applied to at least one of the following products or products with at least one of the following functions:

1) treatment or adjuvant treatment of non-small cell lung cancer;

2) enhancing the curative effect of the single immune medicine on the non-small cell lung cancer;

3) combined with immune single medicine to treat non-small cell lung cancer.

The anti-IL-6 antibody is a substance that inhibits the expression of IL-6.

The application of the anti-IL-6 antibody and the medicines adopted by the non-small cell lung cancer immune single-medicine treatment in at least one of the following or preparing a product with at least one of the following functions is also within the protection scope of the invention:

1) treatment or adjuvant treatment of non-small cell lung cancer;

2) enhancing the curative effect of the single immune medicine on the non-small cell lung cancer;

3) combined with immune single medicine to treat non-small cell lung cancer.

In the above application, the non-small cell lung cancer is squamous cell carcinoma non-small cell lung cancer or non-squamous cell carcinoma non-small cell lung cancer; in embodiments of the invention, squamous cell carcinoma non-small cell lung cancer is exemplified by squamous cell lung carcinoma, and non-squamous cell carcinoma non-small cell lung cancer is exemplified by adenocarcinoma of the lung.

In the above application, the treatment is immunotherapy;

or the medicament adopted by the immune single-drug therapy is a PD-1 inhibitor and/or a PD-L1 inhibitor.

It is another object of the invention to provide a product having at least one of the following functions.

The product provided by the invention is a medicament for IL-6 antibody and non-small cell lung cancer immunization single-drug therapy;

the immune single medicine is a PD-1 inhibitor and/or a PD-L1 inhibitor.

The PD-1 inhibitor may be an anti-PD-1 antibody;

the PD-L1 inhibitor may be an anti-PD-L1 antibody.

Experiments prove that the IL-6 has the potential of predicting the curative effect of the non-small cell lung cancer immune single-drug therapy, and the anti-IL-6 antibody can enhance the anti-tumor effect of the immune therapy by relieving the immune suppression state of an organism.

Drawings

FIG. 1 is a graph showing the plasma IL-6 protein concentration predicted the efficacy of NSCLC immune monotherapy.

FIG. 2 is a representative plot of the staining intensity grading for immunohistochemical techniques to detect IL-6 protein expression.

FIG. 3 is a graph showing the expression of IL-6 protein in tissues predicting the efficacy of NSCLC immunotherapy.

FIG. 4 shows the anti-tumor treatment and efficacy evaluation of tumor-bearing mice.

Detailed Description

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

EXAMPLE 1 use of IL-6 to predict the efficacy of non-Small cell Lung cancer immunotherapy

Case selection in the examples:

this study is a retrospective, non-interventional clinical study. The study was approved by the ethical Committee of the tumor Hospital, Chinese academy of medicine (accession No.: 19/147-1925), conducted on the basis of the declaration of Helsinki, and informed consent was obtained from all subjects.

The study was mainly included in patients with advanced non-small cell lung cancer who received anti-PD-1 antibody therapy at the oncology hospital of the chinese medical academy of sciences from 2018, month 1 to 2019, month 12. The grouping standard is as follows: 1) clinically diagnosing a limited or advanced stage of non-small cell lung cancer patient; 2) the first receiving immunotherapy, but not limited to the number of treatment lines. Exclusion criteria were 1) thymus carcinoma, pleural mesothelioma, and other types of breast tumors; 2) blood specimens were treated without baseline. Patients enrolled in the study received anti-PD-1 antibody treatment once every two/three weeks (3 mg/kg or 240 mg/dose for nivolumab, once every two weeks; 200 mg/dose for each of palbociclumab, certolizumab, and teriepril mab, once every three weeks). Usually, the patient is subjected to neck, chest and abdomen enhanced CT to evaluate the treatment effect once every six weeks, and if necessary, the skull enhanced MRI is added to complete the treatment effect evaluation.

The general conditions that were included in the patients in this study included the age at first visit, sex, ECOG PS score, smoking status, type of pathology, type of gene mutation. Clinical data include the number of immunotherapy lines and history of antibiotic treatment. The history of antibiotic treatment is limited to use 1 week prior to receiving immunotherapy until the time period of progression of the immunotherapeutic disease.

The Evaluation of the efficacy of patients during treatment was evaluated according to the Solid tumor efficacy Evaluation Criteria version 1.1 (Response Evaluation Criteria in Solid Tumors, RECIST version 1.1). Efficacy measures include Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD).

Progression-free survival (PFS) is defined as the time from the start of a patient receiving an immune monotherapy until disease progression or death.

The above data are obtained by inquiring the medical record of hospitalization and telephone follow-up. The last follow-up time for this study was 2021 year, 1 month, 2 days.

Peripheral blood samples of patients at the baseline of the immunization monotherapy were collected at 5ml for this study and stored using EDTA anticoagulant BD blood collection tubes. The collected blood was allowed to stand for 10 minutes, then centrifuged (4 ℃, 3000rmp, 10min), and finally the upper plasma was stored in a freezer at-80 ℃.

The research collects the puncture tissue specimen before the immune single-drug therapy of the patient, and the specimen is immediately taken according to the operation standard after being separated from the body, and is embedded in the wax block. All the tissue specimens were punctured and the pathological tissue sections obtained were confirmed to be non-small cell lung cancer. The specimen acquisition and handling procedures were approved by the ethical committee of the tumor hospital, the academy of medical sciences, china. The providers of the specimens all gave their informed consent.

First, the expression level of IL-6 in plasma is a negative prediction index of the curative effect of immune single drug treatment

A total of 45 non-small cell lung cancer patients were enrolled in the study and the baseline data is detailed in Table 1.

Table 1 shows the baseline data

1. Measurement of IL-6 protein concentration in plasma of 45 non-Small cell Lung cancer patients

The expression level of IL-6 protein in the baseline plasma of 45 non-small cell lung cancer patients was measured by means of a Human IL-6ELISA kit (product of Abcam, Cat # ab46042) using an enzyme-linked immunosorbent assay (ELISA) technique. The GeneBank accession number of the IL-6 gene was NM-000600.5 (filing date 2021, 8/9).

The results are shown in FIGS. 1A, 1B and Table 2, where PR is partial remission, SD is disease stable, PD is disease progression, Non-PD is partial remission or disease stable, and the baseline plasma IL-6 concentration profile is in the range of 1.74-89.14 pg/ml. The expression level of IL-6 was significantly higher in patients in the disease progression group (p 0.0138 and p 0.0041) (fig. 1A and 1B).

TABLE 2 progression free survival time after treatment of 45 non-small cell Lung cancer patients and the concentration of IL-6 protein in baseline plasma

In the above table, 1 in the progression status in column 3 indicates relapse within the follow-up time of column 4, and 0 indicates no relapse or missed follow-up within the follow-up time of column 4.

2. ROC curve

ROC curves were plotted in combination with patient baseline plasma IL-6 protein concentration, progression status and progression-free survival time. The results are shown in FIG. 1C, with an AUC of 0.779.

3. Survival curve

The patients in the group were divided into a group with high baseline IL-6 expression level (higher than 11.150pg/ml) and a group with low baseline IL-6 expression level (lower than or equal to 11.150pg/ml) according to the optimal cut-off value (IL-6 concentration of 11.150 pg/ml).

Survival curves were plotted from progression status and progression-free survival time, and the results are shown in fig. 1D, and the analysis results suggest that progression-free survival rate was significantly increased (p 0.0142) in the low IL-6 expression level group (low expression) at the same follow-up time as compared to the high IL-6 expression level group (high expression) at baseline (fig. 1D).

4. One-factor and multi-factor analysis

The concentration of IL-6 protein in baseline plasma, the type of pathology, the type of genetic mutation and the number of immunotherapy lines were independent factors affecting the therapeutic effect by single and multifactorial analysis (table 3).

TABLE 3 Single and Multi-factor analysis for predicting immune monotherapy PFS

Whereas baseline plasma IL-6 expression levels are independent risk factors affecting PFS (p < 0.001, HR 1.079, 95% CI [1.044-1.115 ]).

II, the expression level of IL-6 in the tumor tissue is a negative prediction index of the curative effect of the immune single drug treatment

A total of 25 patients with non-small cell lung cancer were enrolled in the study and the baseline data is detailed in Table 4.

Table 4 shows the baseline data

1. Measurement of IL-6 protein concentration in tissues of 25 non-Small cell Lung cancer patients

The expression of IL-6 protein in the punctured tissues (baseline tumor tissues) of 25 patients with non-small cell lung cancer was examined by Human anti-IL-6monoclonal antibody (product of CST, Cat #12153) using an Immunohistochemical (IHC) technique, wherein the IL-6 antibody was used at a concentration of 1:200, and the expression level was indicated by an IL-6 staining score, and the expression level was high.

IL-6 expression was scored according to the following principle: staining score (IL-6 staining score) × staining intensity score × percentage of positive tumor cells × 100. Wherein the staining intensity score is: no color development was 0 (negative), pale yellow was 1 (weak positive), yellow was 2 (medium positive), and tan was 3 (strong positive) (fig. 2); percentage of positive tumor cells ten randomly selected fields of view were examined under high power microscopy (x 400), and the percentage of positive tumor cells in the field was calculated by counting the percentage of tumor cells within the field that were stain-positive (weak positive + medium positive + strong positive) to all tumor cells within the field, and the average of the percentages of ten field-positive tumor cells was used as the percentage of positive tumor cells.

As a result, as shown in fig. 3 and table 5, IL-6 expression was significantly high in the disease progression group patients (p ═ 0.0131 and p ═ 0.0024) (fig. 3A and fig. 3B).

Table 5 shows the staining score and progression-free survival of IL-6 in plasma of 25 non-small cell lung cancer patients

In the above table, 1 in the progression status in column 3 indicates relapse within the follow-up time of column 4, and 0 indicates no relapse or missed follow-up within the follow-up time of column 4.

2. ROC curve

ROC curves were plotted in combination with the patient baseline tissue IL-6 staining score, progression status and progression free survival time. As shown in fig. 3C, AUC was 0.790.

3. Survival curve

The patients in the cohort were assigned a high baseline IL-6 expression level (above 120) and a low baseline IL-6 expression level (below or equal to 120) based on the optimal cut-off (IL-6 staining score of 120).

Survival curves were plotted based on progression status and progression-free survival time, and the results are shown in FIG. 3D, and the analysis results suggest that progression-free survival was significantly increased (p < 0.001) in the group with low IL-6 expression levels at the same follow-up time.

4. One-factor and multi-factor analysis

By single and multifactorial analysis, the expression level of IL-6 in tumor tissue, the type of pathology, the stage of disease and the number of immunotherapy lines were independent factors affecting the therapeutic effect (Table 6).

TABLE 6 Single and Multi-factor analysis of PFS

While the expression level of IL-6 in baseline tumor tissue is an independent risk factor for PFS (p 0.017, HR1.059, 95% CI [0.996-1.092 ]).

Therefore, the curative effect of the immune single-drug therapy of the non-small cell lung cancer patient to be detected can be predicted or assisted to be predicted by detecting the expression quantity of IL-6 in the baseline plasma or the baseline tumor tissue of the non-small cell lung cancer patient to be detected, and the judgment standard is as follows:

the curative effect of the immune single medicine treatment of the patient to be detected in the IL-6 low expression group is better than or better than the candidate of the patient to be detected in the IL-6 high expression group;

the efficacy of the immune monotherapy is reflected in the progression-free survival rate or the progression-free survival time; at the same follow-up time, the progression-free survival rate of the test patients in the high expression group is less than or the candidates are less than that of the test patients in the low expression group.

The expression level of IL-6 in the tumor tissue was indicated by a staining score.

Example 2 synergistic enhancement of the antitumor Effect of immunotherapy with the combination of anti-IL-6 antibodies

1. Selection of cell lines and animals

The mouse KLN205 cell line used in the research is from American ATCC cell resource center, and the mouse LA795 cell line is from the cell resource center of the institute of basic medicine of Chinese academy of medical sciences.

The mice used in this study were male DBA-2J mice and female 615 mice, 5 to 6 weeks old, purchased from the institute of hematological diseases, beijing, waukang, and tianjin, respectively. Mice used for the experiments were all housed in an SPF-grade environment. All procedures in the study were strictly in compliance with the regulations set by the animal ethics Committee.

2. Mouse lung adenocarcinoma subcutaneous transplantation tumor model

A female 615 mouse aged 5 to 6 weeks is used for transplanting a mouse lung adenocarcinoma cell line LA 795-derived tumor block subcutaneously to establish a tumor-bearing mouse model, and the number of the tumor-bearing mouse models is 25. The size of the tumor was measured every three days using a vernier caliper (see the literature "Chengming Liu, Sufei Zheng, Runsen Jin, et al. the super efficacy of anti-PD-1/PD-L1 immunology in KRAS-mutant non-small cell luminescence reactor and amplified immunogenicity. cancer Lett.2020; 470: 95-105.").

The volume of the tumor is calculated by the formula: volume is longer diameter and shorter diameter²/2

3. Mouse lung squamous carcinoma subcutaneous transplantation tumor model

A male DBA-2J mouse with the age of 5-6 weeks is used for transplanting tumor blocks derived from a mouse lung squamous carcinoma cell line KLN205 subcutaneously to establish a tumor-bearing mouse model, and the number of the tumor-bearing mouse models is 25. The size of the tumor was measured every three days using a vernier caliper (see the literature "Chengming Liu, Sufei Zheng, Runsen Jin, et al. the super efficacy of anti-PD-1/PD-L1 immunology in KRAS-mutant non-small cell luminescence reactor and amplified immunogenicity. cancer Lett.2020; 470: 95-105.").

The volume of the tumor is calculated by the formula: volume is longer diameter and shorter diameter²/2

4. Antitumor treatment of tumor-bearing mice

When the maximum diameter of the mouse tumor is about 0.5cm, the mouse tumor is randomly divided into five groups according to the sizes of the mouse tumors, and the mice are subjected to different treatment modes:

(1) control group: 100ul of phosphate buffered saline (product of Kaiky corporation, China, 1 XPBS (0.1M, pH7.4), Cat # KGB5001) was intraperitoneally injected into each mouse on days 1, 4, 7, and 10 from the start of administration, respectively.

(2) anti-IL-6monoclonal antibody group: 100ul of anti-IL-6 mab (product of BioXell, Inc., USA, InVivoMab anti-mouse IL-6, Cat # BE0046) was intraperitoneally injected into each mouse on days 1, 4, 7, and 10, respectively, from the start of the administration;

(3) anti-PD-L1 mab group: 100ul of anti-PD-L1 mab (product of BioXell, Inc., USA, InVivoMab anti-mouse PD-L1, Cat # BE0101) was intraperitoneally injected into each mouse on days 1, 4, 7, and 10 of the initial dose;

(4) anti-PD-L1 monoclonal antibody combined with IL-6monoclonal antibody group: 100ul of anti-PD-L1 mab (product of BioXell, USA, InVivoMab anti-mouse PD-L1, Cat # BE0101) and 100ul of anti-IL-6 mab (product of BioXell, USA, InVivoMab anti-mouse IL-6, Cat # BE0046) were intraperitoneally injected into each mouse on days 1, 4, 7, and 10, respectively, from the start of the administration;

(5) anti-PD-L1 mab in combination with paclitaxel: 100ul of anti-PD-L1 mab (product of BioXell, USA, InVivoMab anti-mouse PD-L1, Cat # BE0101) was intraperitoneally administered to each mouse on days 1, 4, 7, and 10, respectively, of the initial administration, and 100ul of Paclitaxel (product of Selleck, China, Paclitaxel, Cat # BE0046) was intraperitoneally administered on days 1, 5, and 9, respectively, of the initial administration;

the 5 monoclonal antibodies per group were administered by intraperitoneal injection, and the specific doses were 10mg/kg of anti-PD-L1 monoclonal antibody (BioXell, InVivoMab anti-mouse PD-L1, Cat # BE0101), 10mg/kg of anti-IL-6monoclonal antibody (BioXell, InVivoMab anti-mouse IL-6, Cat # S1150), and 20mg/kg of Paclitaxel (Selleck, China, Paclitaxel, Cat # BE 0046).

Measuring the major diameter and the minor diameter of subcutaneous tumor of the mouse by using a vernier caliper every two days, and calculating the volume as the major diameter and the minor diameter²And/2, using tumor volume to draw growth curves and observing survival of each group of mice. End-point events were determined as tumors growing to a maximum diameter of 2cm, mice losing more than 2g weight, or death. After the experiment is finished, the dead animals are dissected and taken out by adopting carbon dioxide anesthesia, so that the pain of the animals is relieved.

The results are as follows:

in the mouse lung adenocarcinoma subcutaneous transplantation tumor model, the anti-IL-6monoclonal antibody group can reduce the tumor growth rate compared with the control group, and after receiving the treatment of the anti-IL-6monoclonal antibody in combination with the anti-PD-L1 monoclonal antibody (referred to as the double-antibody treatment group for short), the tumor growth rate and size are both significantly reduced compared with those of the single-drug treatment group (the anti-IL-6monoclonal antibody group or the anti-PD-L1 monoclonal antibody group) (fig. 4A and 4B).

In the mouse lung squamous carcinoma subcutaneous transplantation tumor model, the anti-IL-6monoclonal antibody group could reduce the tumor growth rate compared with the control group, and the tumor growth rate and size were also found to be significantly reduced after receiving the treatment of the double-antibody treatment group compared with the single-drug treatment group (the anti-IL-6monoclonal antibody group or the anti-PD-L1 monoclonal antibody group) (FIGS. 4C and 4D).

However, there was no statistical difference in the growth rate of the mouse tumor between the double-antibody treatment group and the anti-PD-L1 mab in combination with paclitaxel.

The results show that the anti-IL-6monoclonal antibody can realize the treatment of lung adenocarcinoma or lung squamous carcinoma, and the anti-IL-6monoclonal antibody can enhance the effect of immunotherapy and anti-tumor by cooperating with the anti-PD-L1 monoclonal antibody.

Claims (9)

1. The application of the substance for detecting the expression level of the IL-6 in at least one of the following or preparing a product with at least one of the following functions:

(1) predicting or assisting in predicting the efficacy of an immune monotherapy for treating non-small cell lung cancer;

(2) predict or assist in predicting the length of progression-free survival after immune monotherapy treatment of non-small cell lung cancer.

2. Use according to claim 1, characterized in that:

the medicines adopted by the immune single-medicine treatment are PD-1 inhibitors and/or PD-L1 inhibitors.

3. Use according to claim 2, characterized in that:

the substance for detecting the expression quantity of the IL-6 is a substance for detecting the expression quantity of the IL-6 in the baseline plasma or the baseline tumor tissue of the patient with the non-small cell lung cancer to be detected;

or the substance for detecting the expression quantity of the IL-6 in the baseline plasma or the baseline tumor tissue of the non-small cell lung cancer patient to be detected is an antibody or other molecules capable of specifically binding to the IL-6.

Use of IL-6 as a marker in the development, screening and/or preparation of an agent for predicting or aiding in the prediction of the efficacy of an immune monotherapy in a non-small cell lung cancer patient.

5. Use of an anti-IL-6 antibody in at least one of the following or in the manufacture of a product having at least one of the following functions:

1) treatment or adjuvant treatment of non-small cell lung cancer;

2) enhancing the curative effect of the single immune medicine on the non-small cell lung cancer;

3) combined with immune single medicine to treat non-small cell lung cancer.

6. The application of the anti-IL-6 antibody and the medicines adopted by the non-small cell lung cancer immune monotherapy in at least one of the following or preparing a product with at least one of the following functions:

1) treatment or adjuvant treatment of non-small cell lung cancer;

2) enhancing the curative effect of the single immune medicine on the non-small cell lung cancer;

3) combined with immune single medicine to treat non-small cell lung cancer.

7. Use according to claim 5 or 6, characterized in that:

the non-small cell lung cancer is squamous cell carcinoma non-small cell lung cancer or non-squamous cell carcinoma non-small cell lung cancer.

8. Use according to any one of claims 5 to 7, characterized in that:

the treatment is immunotherapy;

or the medicament adopted by the immune single-drug therapy is a PD-1 inhibitor and/or a PD-L1 inhibitor.

9. A product which is a medicament for at least one of an IL-6 antibody and a non-small cell lung cancer immunotherapy;

the medicines adopted by the immune single-medicine treatment are PD-1 inhibitors and/or PD-L1 inhibitors.

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