A method for predicting the therapeutic effect of cancer immunotherapy and / or the prognosis of cancer patients.

Abstract

The inventors' primary objective was to provide a technology that can predict the therapeutic effect of cancer immunotherapy in subjects with cancer, and / or the prognosis of subjects with cancer who have received, are currently receiving, or may receive cancer immunotherapy in the future. [Solution] The present inventors have found that a method comprising (a) obtaining reflection values ​​of CRP, Alb, and lymphocyte count in a blood sample taken from a subject, and (b) classifying the subject based on the reflection values ​​of CRP, Alb, and lymphocyte count, can predict the therapeutic effect of cancer immunotherapy in a subject with cancer, and / or the prognosis of a subject with cancer who has received, is currently receiving, or may receive cancer immunotherapy.

Description

Technical Field

[0001] The present disclosure relates to a method and the like for predicting the therapeutic effect of cancer immunotherapy in a subject having cancer, and / or the prognosis of a subject having cancer who has received, is currently receiving, or may receive cancer immunotherapy.

Background Art

[0002] Cancer is one of the leading causes of death worldwide, and surgical operation, radiation therapy, chemotherapy, targeted therapy, cancer immunotherapy and the like are used as therapeutic methods therefor. Cancer immunotherapy has attracted attention as an innovative therapeutic method that aims to activate the patient's immune system and specifically eliminate tumor cells. Particularly in recent years, immune checkpoint inhibitors have been developed as cancer immunotherapeutic agents and have attracted significant attention. Currently, immune checkpoint inhibitors widely used in clinical practice are anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] As mentioned above, immune checkpoint inhibitors, which have a fundamentally different mechanism of action from conventional anticancer drugs, have shown remarkable therapeutic effects against various types of tumors. However, cancer immunotherapy does not show the same therapeutic effect in all patients; in some patients, the therapeutic effect is limited or no effect is observed at all. Therefore, predicting the therapeutic effect of cancer immunotherapy and making appropriate patient selections is extremely important.

[0005] To date, various biomarkers that can be easily calculated from blood data and nutritional status have been reported. The neutrophil-to-lymphocyte ratio (NLR), calculated using peripheral blood, is used as a predictive marker for the prognosis and treatment effectiveness of various cancers. The Glasgow Prognostic Score (GPS) is a cumulative prognostic score based on systemic inflammatory response and albumin levels. Subsequently, based on the finding that ALB alone does not correlate with prognosis, a new term, modified GPS (mGPS), was proposed.

[0006] However, cancer immunotherapy is a relatively recent treatment method, and partly due to the insufficient accumulation of data from cases where it has been applied, biomarkers that can accurately predict the effectiveness of cancer immunotherapy have not yet been established. Furthermore, accurately predicting the prognosis of patients receiving cancer immunotherapy is also important in determining treatment strategies and managing patients.

[0007] The inventors' primary objective was to provide a technology that can predict the therapeutic effect of cancer immunotherapy in subjects with cancer, and / or the prognosis of subjects with cancer who have received, are currently receiving, or may receive cancer immunotherapy in the future. [Means for solving the problem]

[0008] The inventors have found that a method comprising (a) obtaining reflective values ​​of CRP, Alb, and lymphocyte count in a blood sample taken from a subject, and (b) classifying the subject based on the reflective values ​​of CRP, Alb, and lymphocyte count, can predict the therapeutic effect of cancer immunotherapy in subjects with cancer, and / or the prognosis of subjects with cancer who have received, are currently receiving, or may receive cancer immunotherapy. Further improvements have led to the completion of this disclosure.

[0009] This disclosure includes, for example, the following subjects: Section 1. A method for predicting the therapeutic effect of cancer immunotherapy in subjects with cancer, and / or the prognosis of subjects with cancer who have received, are currently receiving, or may receive cancer immunotherapy in the future, (a) A step of obtaining the CRP reflection value, the albumin reflection value, and the lymphocyte count reflection value in the blood sample taken from the subject, (b) A step of classifying the subjects based on the CRP reflection value, the Alb reflection value, and the lymphocyte count reflection value, A method by which the therapeutic effect and / or prognosis can be predicted based on the aforementioned classification. Section 2. The above criteria apply to the following: Classification (1): When the CRP reflection value is below threshold A, and the lymphocyte count reflection value is above threshold C. Classification (2): When the CRP reflection value is below threshold A, and the lymphocyte count reflection value is less than threshold C. Classification (3): When the CRP reflection value is greater than threshold A, the albumin reflection value is greater than or equal to threshold B, and the lymphocyte count reflection value is greater than or equal to threshold C. Classification (4): When the CRP reflection value is greater than threshold A, the albumin reflection value is greater than or equal to threshold B, and the lymphocyte count reflection value is less than threshold C. Classification (5): When the CRP reflection value is greater than threshold A, the albumin reflection value is less than threshold B, and the lymphocyte count reflection value is greater than or equal to threshold C. Classification (6): When the CRP reflection value is greater than threshold A, the albumin reflection value is less than threshold B, and the lymphocyte count reflection value is less than threshold C. The method described in item 1, classified according to the following: Section 3. The method according to item 2, wherein in at least one pair of classifications (1) and (2), classification (3) and (4), and classification (5) and (6), the classification with the smaller classification number is predicted to have a higher probability of response to the cancer immunotherapy and / or a better prognosis for the subject. Section 4. A method for predicting the therapeutic effect of cancer immunotherapy in subjects with cancer, The following criteria: Classification (1): imGPS(Immune-modified Glasgow Prognostic Score)=0 Classification (2) or Classification (3): imGPS=1 Classification (4) or Classification (5): imGPS=2 Classification (6):imGPS=3 The process further includes the step of calculating the target imGPS according to the above, The method according to item 2, wherein a smaller imGPS value is predicted to indicate a higher likelihood of response to cancer immunotherapy. Section 5. A method for predicting the prognosis of cancer patients who have received, are currently receiving, or are likely to receive cancer immunotherapy, The following criteria: Classification (1): imGPS(Immune-modified Glasgow Prognostic Score)=0 Classification (2) or Classification (3): imGPS=1 Classification (4) or Classification (5): imGPS=2 Classification (6):imGPS=3 The process further includes the step of calculating the target imGPS according to the above, The method according to item 2, wherein a smaller imGPS value is predicted to indicate a better prognosis. Section 6. The reflected value of CRP is the serum CRP concentration, the reflected value of Alb is the serum Alb concentration, and the reflected value of the lymphocyte count is the absolute lymphocyte count, the threshold A is 0.7 to 1.5 mg / dL, the threshold B is 2.5 to 5.5 g / dL, and the threshold C is 800 to 1900 count / μL, the method according to any one of Items 1 to 5. Item 7. The method according to any one of Items 1 to 7, wherein the cancer immunotherapy is administration of an immune checkpoint inhibitor. Item 8. The method according to Item 7, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody. Item 9. The method according to any one of Items 1 to 8, wherein the subject is a subject having head and neck cancer. Effects of the Invention

[0010] According to the present disclosure, a technique capable of predicting the therapeutic effect of cancer immunotherapy in a subject having cancer, and / or the prognosis of a subject having cancer who has received, is currently receiving, or may receive cancer immunotherapy can be provided. Brief Description of the Drawings

[0011] [Figure 1] The ROC curve for NLR is shown. [Figure 2]The following eight biomarkers were evaluated for objective response rates (ORR): CRP (≤1: n = 37, 1<: n = 17), ALB (<3.5: n = 23, 3.5≦: n = 31), lymphocyte count (≤1250: n = 17, 1250<: n = 37), NLR (<6.589: n = 38, 6.589≦: n = 16), mGPS (0: n = 37, 1: n = 5, 2: n = 12), imGPS (0: n = 14, 1: n = 21, 2: n = 9, 3: n = 10). **: p < 0.01; *: p < 0.05. [Figure 3] The prognosis for all cases (total) is shown. OS: overall survival, PFS: progression-free survival. The median OS was 14.5 months, and the median PFS was 3.4 months. [Figure 4] This report presents the results of an investigation into the correlation between age, CPS, and whether or not chemotherapy was administered, and the prognosis after pembrolizumab administration. Overall survival (OS) and progression-free survival (PFS) were evaluated based on age (under 70 years or 70 years or older), CPS (less than 1, 1 to less than 20, or 20 or more), and whether or not chemotherapy was administered. [Figure 5] This report presents the results of an investigation into the correlation between CRP, ALB, and lymphocyte counts and prognosis after pembrolizumab administration. Overall survival (OS) and progression-free survival (PFS) were evaluated based on CRP and ALB levels, as well as lymphocyte counts. CRP (≦1: n = 37, 1<: n = 17), ALB (<3.5: n = 23, 3.5≦: n = 31), lymphocyte count (≦1250: n = 17, 1250<: n = 37). ***, p < 0.001; **, p < 0.01; *, p < 0.05. [Figure 6]This report presents the results of an investigation into the correlation between NLR, mGPS, and imGPS with prognosis after pembrolizumab administration. Overall survival (OS) and progression-free survival (PFS) were assessed based on NLR, mGPS, and imGPS. NLR (<6.589: n = 38, 6.589≦: n = 16), mGPS (0: n = 37, 1: n = 5, 2: n = 12), imGPS (0: n = 14, 1: n = 21, 2: n = 9, 3: n = 10). **, p < 0.01; *, p < 0.05. [Figure 7] This report presents the results of a separate investigation into the correlation between pembrolizumab administration and prognosis in the pembrolizumab monotherapy group (alone) and the pembrolizumab combination therapy group (combo). Overall survival (OS) was assessed for both groups based on CRP and ALB levels, as well as lymphocyte count. **, p < 0.01; *, p < 0.05. [Figure 8] This report presents the results of a separate investigation into the correlation between pembrolizumab administration and prognosis in the pembrolizumab monotherapy group (alone) and the pembrolizumab combination therapy group (combo). For both groups, progression-free survival (PFS) was evaluated based on CRP and ALB levels, as well as lymphocyte count. *p < 0.01. [Figure 9] This report presents the results of a separate investigation into the correlation between pembrolizumab administration and prognosis in the pembrolizumab monotherapy group (alone) and the pembrolizumab combination therapy group (combo). Overall survival (OS) was assessed for both the pembrolizumab monotherapy group and the pembrolizumab combination therapy group based on NLR, mGPS, and imGPS. ***, p < 0.001; *, p < 0.05. [Figure 10]This report presents the results of a separate investigation into the correlation between pembrolizumab administration and prognosis in the pembrolizumab monotherapy group (alone) and the chemotherapy combination group (combo). Progression-free survival (PFS) was evaluated for each group based on NLR, mGPS, and imGPS. ***, p < 0.001; **, p < 0.01; *, p < 0.05 [Modes for carrying out the invention]

[0012] The embodiments included in this disclosure will be described in more detail below. This disclosure preferably includes, but is not limited to, methods for predicting the therapeutic effect of cancer immunotherapy in subjects with cancer, and methods for predicting the prognosis of subjects with cancer who have received, are currently receiving, or may receive cancer immunotherapy. This disclosure includes everything disclosed herein and that can be recognized by those skilled in the art.

[0013] The methods for predicting therapeutic effects and / or prognosis included in this disclosure are methods for predicting the therapeutic effects of cancer immunotherapy in subjects with cancer, and / or the prognosis of subjects with cancer who have received, are currently receiving, or may receive cancer immunotherapy. (a) A step of obtaining the CRP reflection value, the albumin reflection value, and the lymphocyte count reflection value in the blood sample taken from the subject, (b) A step of classifying the subjects based on the CRP reflection value, the Alb reflection value, and the lymphocyte count reflection value, A method in which the therapeutic effect and / or prognosis can be predicted based on the aforementioned classification. Hereinafter, such method as it is included in this disclosure may be referred to as the "method of this disclosure."

[0014] In this disclosure, the term "cancer" includes cancer, neoplasms, and malignant tumors. The cancers to which the technology of this disclosure applies are not particularly limited. Examples of cancers include head and neck cancer, gastric cancer, colorectal cancer (colon cancer, rectal cancer), esophageal cancer, liver cancer, pancreatic cancer, gallbladder cancer, malignant melanoma, kidney cancer, breast cancer, mesothelioma, bladder cancer, disseminated intraperitoneal cancer, lung cancer, soft tissue sarcoma, osteosarcoma, brain tumor, neuroblastoma, leukemia, lymphoma, prostate cancer, retinoblastoma, ciliary tumor, basal cell carcinoma, squamous cell carcinoma, malignant soft tissue tumor, chondrosarcoma, ovarian cancer, endometrial cancer, and cervical cancer. While not particularly limited, the technology of this disclosure is preferably applied to subjects with head and neck cancer, and particularly preferably to subjects with recurrent or metastatic head and neck cancer.

[0015] Cancer immunotherapy is a treatment method aimed at attacking and eliminating cancer cells by activating or regulating the patient's own immune system. Specific examples of cancer immunotherapy include, for example, administration of immune checkpoint inhibitors, cancer vaccine therapy, T cell receptor (TCR) T cell (TCR-T) therapy, chimeric antigen receptor (CAR) T cell (CAR-T) therapy, and cytokine therapy. While not particularly limited, in the technology disclosed herein, cancer immunotherapy is particularly preferably the administration of immune checkpoint inhibitors.

[0016] Immune checkpoint inhibitors are drugs that target at least one checkpoint molecule in the immune system (e.g., PD-1, PD-L1, and CTLA-4) and enhance the anti-tumor immune response of T cells by releasing its suppressive signal. Normally, immune checkpoint molecules play a role in preventing autoimmune reactions and suppressing excessive activation of the immune response. However, some cancer cells are known to use these checkpoint molecules to evade immune surveillance and suppress T cell function. Immune checkpoint inhibitors release this immunosuppression and promote the attack of T cells on tumor cells. Specifically, immune checkpoint inhibitors include at least one selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors, and preferably at least one selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies. The antibodies may be polyclonal or monoclonal antibodies, and monoclonal antibodies are preferred. More specifically, anti-PD-1 antibodies include, for example, nivolumab and pembrolizumab. Examples of anti-PD-L1 antibodies include atezolizumab, durvalumab, and avelumab. Examples of anti-CTLA-4 antibodies include ipilimumab and tremelimumab. While not particularly limited, in the technologies of this disclosure, the immune checkpoint inhibitor is more preferably an anti-PD-1 antibody and / or an anti-PD-L1 antibody, even more preferably an anti-PD-1 antibody, and particularly preferably pembrolizumab.

[0017] PD-1 (Programmed cell death-1) is a receptor expressed on the surface of activated T cells, and when PD-1 binds to its ligand, the immune response by T cells is suppressed. In normal T cells, the interaction between PD-1 and PD-L1 plays a role in suppressing excessive immune responses. On the other hand, some cancer cells and surrounding cells express PD-L1 (Programmed cell death-ligand 1), a ligand for PD-1, on their cell surface. These cells suppress T cell activity and evade T cell attack by binding their own PD-L1 to PD-1 on the surface of T cells. Anti-PD-1 antibodies and anti-PD-L1 antibodies evade the suppression of T cell activity by inhibiting the binding of PD-1 and PD-L1, thereby promoting T cell activation and enhancing the attack on cancer cells. Additionally, CTLA-4 (Cytotoxic T lymphocyte antigen-4) is also a receptor expressed on the surface of T cells, and when CTLA-4 binds to its ligand, T cell activation is suppressed. Anti-CTLA-4 antibodies enhance T cell activation and attack cancer cells by inhibiting the binding of CTLA-4 to its ligand.

[0018] Generally, objective indicators such as "RECIST (Response Evaluation Criteria in Solid Tumors)" are used to evaluate treatment effectiveness, and these are classified into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Although not particularly limited, in this disclosure, the prediction of treatment effectiveness may specifically refer to the prediction of the likelihood of a response. In this disclosure, a response may refer to either a complete response or a partial response. A complete response is a state in which all tumor lesions have disappeared on imaging. A partial response is a state in which the size of the tumor has decreased by a certain percentage or more (usually 30% or more). Stable disease is a state in which there is no significant change in the size of the tumor, but no increase in size is observed. Progression is a state in which the tumor has increased in size or new lesions have appeared.

[0019] Prognosis refers to the medical outlook regarding the progression of the disease and the final outcome (survival, recurrence, occurrence of complications, etc.) in patients with a disease. Indicators for evaluating cancer prognosis include, for example, overall survival (OS), progression-free survival (PFS), disease-specific survival rate, and recurrence rate. Although not particularly limited, the prognosis to be predicted in the technology disclosed herein is preferably overall survival (OS) and / or progression-free survival (PFS), and more preferably overall survival (OS) and / or progression-free survival (PFS) after receiving cancer immunotherapy.

[0020] In this disclosure, a blood sample taken from a subject means a sample containing blood taken from a living organism. The blood sample may be whole blood, serum, plasma, or a sample containing specific blood components (white blood cells, red blood cells, platelets, etc.). It may also be fractionated by methods such as centrifugation and / or filtration. Although not particularly limited, in the techniques of this disclosure, the blood sample is particularly preferably a sample containing serum and / or white blood cells (especially lymphocytes).

[0021] In this disclosure, the CRP reflection value refers to an index calculated based on the concentration of C-reactive protein (CRP) in a blood sample. CRP is an acute-phase protein produced in the liver, and its blood concentration may increase in response to systemic inflammatory responses associated with infection, tissue damage, malignant tumors, etc. In cancer patients, elevated CRP has been reported to reflect chronic inflammation and immunosuppression in the tumor microenvironment. Specifically, serum CRP concentration can be cited as an example of a CRP reflection value.

[0022] In the technology of this disclosure, the method for obtaining the CRP reflection value is not particularly limited as long as the desired effect is obtained. For example, the CRP reflection value can be obtained using at least one method selected from the group consisting of immunoturbidimetry, immunocolorimetric methods (enzyme-linked immunosorbent assay, ELISA), and latex agglutination immunoassay. Although not particularly limited, in the technology of this disclosure, the CRP reflection value is preferably obtained by immunoturbidimetry. The act of obtaining the CRP reflection value measured by an external testing laboratory is also included in "obtaining" in this disclosure.

[0023] In this disclosure, the Alb reflection value refers to an index calculated based on the albumin (Alb) concentration in a blood sample. Alb plays a role in maintaining the colloid osmotic pressure of plasma and is involved in the transport of various hormones, drugs, fatty acids, etc. The Alb concentration in a blood sample can serve as an indicator reflecting nutritional status, liver function, inflammatory response, etc. In cancer patients, low Alb levels (hypoalbuminemia) have been reported to indicate a deterioration of systemic inflammatory response and nutritional status. Specifically, an example of an Alb reflection value is serum Alb concentration.

[0024] In the technology of this disclosure, the method for obtaining the reflected value of albumin is not particularly limited, as long as the desired effect is obtained. For example, the reflected value of albumin can be obtained using at least one method selected from the group consisting of the bromocresol purple (BCP) method, the modified BCP method, the bromocresol green (BCG) method, the biuret method, and immunoturbidimetry. Although not particularly limited, in the technology of this disclosure, it is preferable that the reflected value of albumin is obtained by at least one method selected from the group consisting of the BCP method, the modified BCP method, and the BCG method. The act of obtaining the reflected value of albumin measured by an external testing laboratory is also included in "obtaining" in this disclosure.

[0025] In this disclosure, the lymphocyte count indicator refers to an index calculated based on the number of lymphocytes in a blood sample. Lymphocytes include immune cells such as T cells, B cells, and NK cells, and play an important role in infection defense and tumor immune responses. Specific examples of lymphocyte count indicators include the lymphocyte percentage (LY%), which is the ratio of lymphocytes to white blood cells; the neutrophil-to-lymphocyte ratio (NLR); the lymphocyte-to-monocyte ratio (LMR); and the absolute lymphocyte count (ALC). While not particularly limited, in the technology of this disclosure, the lymphocyte count indicator is preferably the absolute lymphocyte count (which may also be simply referred to as "lymphocyte count" in this disclosure). The absolute lymphocyte count is a value that indicates the number of lymphocytes in whole blood.

[0026] In the technology of this disclosure, the method for obtaining the lymphocyte count is not particularly limited, as long as the desired effect is achieved. For example, the lymphocyte count can be obtained using at least one method selected from the group consisting of a method using an automated hematology analyzer and flow cytometry. Although not particularly limited, in the technology of this disclosure, it is preferable that the lymphocyte count is obtained by a method using an automated hematology analyzer. The act of obtaining the lymphocyte count measured by an external testing laboratory is also included in "obtaining" in this disclosure.

[0027] In the technology of this disclosure, the subjects are classified based on the reflected value of CRP, the reflected value of Alb, and the reflected value of lymphocyte count, and the therapeutic effect and / or prognosis are predicted based on this classification.

[0028] From the standpoint of prediction accuracy, it is preferable that the above-mentioned targets be classified according to the following criteria: Classification (1): When the CRP reflection value is below threshold A, and the lymphocyte count reflection value is above threshold C. Classification (2): When the CRP reflection value is below threshold A, and the lymphocyte count reflection value is less than threshold C. Classification (3): When the CRP reflection value is greater than threshold A, the albumin reflection value is greater than or equal to threshold B, and the lymphocyte count reflection value is greater than or equal to threshold C. Classification (4): When the CRP reflection value is greater than threshold A, the Albumin reflection value is greater than or equal to threshold B, and the lymphocyte count reflection value is less than threshold C. Classification (5): When the CRP reflection value is greater than threshold A, the albumin reflection value is less than threshold B, and the lymphocyte count reflection value is greater than or equal to threshold C. Classification (6): When the CRP reflection value is greater than threshold A, the Albumin reflection value is less than threshold B, and the lymphocyte count reflection value is less than threshold C.

[0029] Note that "greater than" and "less than" do not include the reference number and are mathematically represented by "<" and ">". "Equal to or greater than" and "equal to or less than" include the reference number and are mathematically represented by "≦" and "≧".

[0030] Insofar as the effects of this disclosure are achieved, the specific values ​​of thresholds A, B, and C are not particularly limited and can be selected as appropriate. For example, thresholds that provide an optimal balance between sensitivity and specificity may be selected based on ROC (Receiver Operatoring Characteristic) curve analysis. Specifically, values ​​that maximize the AUC (Area Under the Curve) in the ROC analysis may be selected.

[0031] When the CRP reflection value is the serum CRP concentration, the threshold A may be, for example, 0.5 to 2.0 mg / dL. The upper or lower limit of the range may be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mg / dL. Although not particularly limited, when the CRP reflection value is the serum CRP concentration, the threshold A is preferably 0.6 to 1.8 mg / dL, more preferably 0.7 to 1.5 mg / dL, even more preferably 0.8 to 1.2 mg / dL, and particularly preferably 1.0 mg / dL.

[0032] When the reflected value of Alb is the serum Alb concentration, the threshold B may be, for example, 1.5 to 7.0 g / dL. The upper or lower limit of the range may be 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7.0 g / dL. Although not particularly limited, when the reflected value of Alb is the serum Alb concentration, the threshold B is preferably 2.0 to 6.0 g / dL, more preferably 2.5 to 5.5 g / dL, even more preferably 3.0 to 4.0 g / dL, and particularly preferably 3.5 g / dL.

[0033] When the value reflecting the lymphocyte count is the absolute lymphocyte count, the threshold C may be, for example, 500 to 2500 count / μL. The upper or lower limit of the range may be 500, 600, 700, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or 2500 count / μL. Although not particularly limited, when the value reflecting the lymphocyte count is the absolute lymphocyte count, the threshold C is preferably 600 to 2200 count / μL, more preferably 800 to 1900 count / μL, even more preferably 1000 to 1500 count / μL, and particularly preferably 1250 count / μL. In this disclosure, the unit "count / μL" may be simply written as " / μL".

[0034] While not particularly limited, when the CRP reflection value is serum CRP concentration, the Alb reflection value is serum Alb concentration, and the lymphocyte count reflection value is absolute lymphocyte count, it is preferable that the threshold A is 0.6~1.8 mg / dL, the threshold B is 2.0~6.0 g / dL, and the threshold C is 600~2200 count / μL; more preferably that the threshold A is 0.7~1.5 mg / dL, the threshold B is 2.5~5.5 g / dL, and the threshold C is 800~1900 count / μL; even more preferably that the threshold A is 0.8~1.2 mg / dL, the threshold B is 3.0~4.0 g / dL, and the threshold C is 1000~1500 count / μL; and it is preferable that the threshold A is 1.0 mg / dL, the threshold B is 3.5 g / dL, and the threshold C is 1250 A value of count / μL is particularly preferred.

[0035] In the technology of this disclosure, it is preferable that in at least one pair of classifications (1) and (2), (3) and (4), and (5) and (6), the classification with the smaller classification number is predicted to have a higher probability of response to cancer immunotherapy and / or a better prognosis for the subject. Specifically, for example, if classification (1) is predicted to have a higher probability of response to cancer immunotherapy and / or a better prognosis for the subject than classification (2), then the treatment effects and / or prognoses predicted by classification (3) and (4) may be the same or different, and similarly, the treatment effects and / or prognoses predicted by classification (5) and (6) may also be the same or different. Furthermore, if, for example, classification (3) is predicted to have a higher probability of responding to cancer immunotherapy than classification (4), and / or the prognosis of the subject is predicted to be better, then the treatment effects and / or prognosis predicted by classification (1) and classification (2) may be the same or different, and similarly, the treatment effects and / or prognosis predicted by classification (5) and classification (6) may be the same or different.

[0036] From the perspective of prediction accuracy, the method of this disclosure is based on the following criteria: Classification (1): imGPS(Immune-modified Glasgow Prognostic Score) = 0 Classification (2) or Classification (3): imGPS = 1 Classification (4) or Classification (5): imGPS = 2 Classification(6):imGPS = 3 It is more preferable to further include a step of calculating the target imGPS according to this.

[0037] In the technology of this disclosure, a smaller imGPS value can be predicted to indicate a higher probability of response to cancer immunotherapy. While not particularly limited, for example, if imGPS = 0, the probability of response may be predicted to be approximately 40-60%, if imGPS = 1, the probability of response may be predicted to be approximately 10-30%, and if imGPS = 2, the probability of response may be predicted to be approximately 5-15%. Preferably, if imGPS = 0, the probability of response may be predicted to be approximately 45-55%, if imGPS = 1, the probability of response may be predicted to be approximately 15-25%, and if imGPS = 2, the probability of response may be predicted to be approximately 5-15%. More preferably, if imGPS = 0, the probability of response may be predicted to be approximately 50%, if imGPS = 1, the probability of response may be predicted to be approximately 20%, and if imGPS = 2, the probability of response may be predicted to be approximately 10%.

[0038] In the technology of this disclosure, a smaller imGPS value may indicate a better prognosis for cancer patients who have received, are currently receiving, or are likely to receive cancer immunotherapy. While not particularly limited, for example, if imGPS = 0, overall survival after cancer immunotherapy is predicted to be 40 months or longer; if imGPS = 1, overall survival is predicted to be approximately 6-15 months; if imGPS = 2, overall survival is predicted to be approximately 6-15 months; and if imGPS = 3, overall survival is predicted to be approximately 3-9 months. It is preferable that when imGPS = 0, the overall survival after receiving cancer immunotherapy is predicted to be 45 months or more; when imGPS = 1, the overall survival after receiving cancer immunotherapy is predicted to be approximately 8 to 14 months; when imGPS = 2, the overall survival after receiving cancer immunotherapy is predicted to be approximately 8 to 14 months; and when imGPS = 3, the overall survival after receiving cancer immunotherapy is predicted to be approximately 4 to 7 months. It is even more preferable that when imGPS = 0, the overall survival after receiving cancer immunotherapy is predicted to be 50 months or more; when imGPS = 1, the overall survival after receiving cancer immunotherapy is predicted to be approximately 12 months; when imGPS = 2, the overall survival after receiving cancer immunotherapy is predicted to be approximately 12 months; and when imGPS = 3, the overall survival after receiving cancer immunotherapy is predicted to be approximately 6 months.

[0039] While not particularly limited, for example, if imGPS = 0, the progression-free survival period after receiving cancer immunotherapy is predicted to be approximately 7-15 months; if imGPS = 1, it is predicted to be approximately 2-8 months; if imGPS = 2, it is predicted to be approximately 0.5-4 months; and if imGPS = 3, it may be predicted to be approximately 0.5-4 months. Preferably, if imGPS = 0, the progression-free survival period after receiving cancer immunotherapy is predicted to be approximately 9-13 months; if imGPS = 1, it is predicted to be approximately 3-6 months; if imGPS = 2, it is predicted to be approximately 1-3 months; and if imGPS = 3, it is predicted to be approximately 1-3 months. It is preferable that when imGPS = 0, the progression-free survival after receiving cancer immunotherapy is predicted to be approximately 11 months; when imGPS = 1, the progression-free survival after receiving cancer immunotherapy is predicted to be approximately 4 months; when imGPS = 2, the progression-free survival after receiving cancer immunotherapy is predicted to be approximately 2 months; and when imGPS = 3, the progression-free survival after receiving cancer immunotherapy is predicted to be approximately 2 months.

[0040] Cancer patients to whom the technology disclosed herein applies may have received, are currently receiving, or be at risk of receiving cancer treatment other than cancer immunotherapy. Cancer patients to whom the technology disclosed herein applies may not have received any cancer treatment other than cancer immunotherapy. Cancer patients to whom the technology disclosed herein applies may receive cancer treatment other than cancer immunotherapy in parallel with cancer immunotherapy, or may receive cancer immunotherapy alone.

[0041] Other cancer treatments besides cancer immunotherapy include surgery, radiotherapy, chemotherapy, molecular targeted therapy, and hormone therapy. While not particularly limited, in the technologies of this disclosure, cancer treatments other than cancer immunotherapy preferably include chemotherapy.

[0042] Specific chemotherapy regimens include, for example, cytotoxic anticancer agents such as paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine; molecularly targeted anticancer agents such as bortezomib, ixavomib, trastuzumab emtansine, brentuximab vedotin, lorlatinib, entrectinib, pemigatinib, polatuzumab vedotin, and enfortumab vedotin; and the administration of at least one anticancer agent selected from fluorouracil, thalidomide, lenalidomide, pomalidomide, and darinaparsin. While not particularly limited, chemotherapy in the techniques of this disclosure preferably includes the administration of a cytotoxic anticancer agent, more preferably the administration of cisplatin or carboplatin, and even more preferably the administration of cisplatin or carboplatin and fluorouracil (5-fluorouracil).

[0043] In this specification, the term “comprising” includes not only “containing” but also “essentially consisting of” and “consisting of.” Furthermore, this disclosure encompasses all combinations of the constituent elements described herein.

[0044] Furthermore, the various characteristics (properties, numerical values, structure, function, etc.) described for each embodiment of this disclosure described above may be combined in any way to identify the subject matter covered by this disclosure. In other words, this disclosure covers all subject matter consisting of any combination of the combinable characteristics described herein. [Examples]

[0045] The embodiments of this disclosure will be described in more detail below with examples, but the embodiments of this disclosure are not limited to the examples below.

[0046] 1. Materials and Methods 1.1. Patient This study included 54 patients with recurrent and metastatic head and neck cancer (RMHNC) who received pembrolizumab treatment at Gifu University Hospital (Japan) between December 2019 and April 2024. Pembrolizumab treatment was administered to RMHNC patients who had no prior chemotherapy history for the target disease. Patients were primarily divided into a pembrolizumab monotherapy group and a pembrolizumab combination therapy group based on their Combined Positive Score (CPS). However, regimens were selected considering not only CPS but also age, Performance Status (PS), and tumor progression rate. In the chemotherapy combination therapy group, cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil was selected depending on renal function, and dose reduction was performed in some cases.

[0047] 1.2. Data Collection and Evaluation Items From blood test data collected immediately before pembrolizumab administration, serum CRP concentration (simply referred to as "CRP" in this example), serum albumin concentration (simply referred to as "ALB" in this example), absolute lymphocyte count (simply referred to as "lymphocyte count" in this example), and neutrophil count were extracted, and NLR, mGPS, and imGPS were calculated. The cutoff value for CRP was set at 1 mg / dL. The cutoff value for ALB was set at 3.5 g / dL. The cutoff value for lymphocyte count was set at 1250 / μL. NLR was calculated as neutrophils / lymphocyte count, and the cutoff value was determined using ROC analysis. The scoring methods for mGPS and imGPS are shown in the table below. As can be seen from the table below, mGPS is calculated based on CRP and ALB, while imGPS is calculated based on CRP, ALB, and lymphocyte count.

[0048] [Table 1]

[0049] The Combined Positive Score (CPS) was calculated by immunostaining tissue samples obtained by biopsy or surgery with an anti-PD-L1 mouse monoclonal antibody (Clone22C3), then dividing the number of positive cells (tumor cells, lymphocytes, and macrophages) by the total number of viable tumor cells and multiplying by 100.

[0050] In this embodiment, treatment efficacy was evaluated based on the Best Overall Response (BOR), and the Overall Response Rate (ORR) represents the proportion of cases with partial response (PR) and complete response (CR) to the total number of cases. The Best Overall Response is one of the indicators used to evaluate the effectiveness of cancer treatment, and refers to the best response shown by the patient during the treatment period. Prognosis was evaluated as overall survival (OS) and progression-free survival (PFS).

[0051] 1.3. Statistical analysis Survival time analysis was performed using the Kaplan-Meier method, and differences between groups were analyzed using the Log-rank test. Differences in ORR between groups were analyzed using the chi-square test. The significance of related parameters was evaluated using the Cox proportional hazards regression model. To evaluate the usefulness of imGPS for prognostic predictors (OS and PFS), ROC analysis was performed and AUC values ​​were calculated. All statistical analyses were performed using EZR (version 3.6.3). In all analyses, a p-value of less than 0.05 was considered statistically significant.

[0052] 2. Results 2.1. Patient Characteristics A total of 54 patients were enrolled (Table 2). The median age was 70 years (range: 37–91 years). Primary sites were diverse, with the most common being the hypopharynx at 27.8%. Pathologically, squamous cell carcinoma (SCC) accounted for 83.3%. 9.3% of cases had a CPS < 1. 55.6% of cases had a CPS of 1 ≤ 20, and 27.8% had a CPS of 20 ≤ 20. Of these cases, 48.1% received pembrolizumab monotherapy (alone), and 51.9% received pembrolizumab in combination with cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil (chemotherapy). The median follow-up period was 10.6 months (range: 0.1–45.2 months).

[0053] NLR, mGPS, and imGPS were calculated from the blood test data of the above patients. The cutoff value for NLR was set to 6.589 based on ROC analysis (AUC: 0.585, 95% CI: 0.43~0.739) (Figure 1). For mGPS, 37 patients scored 0, 5 patients scored 1, and 12 patients scored 2. For imGPS, 14 patients scored 0, 21 patients scored 1, 9 patients scored 2, and 10 patients scored 3.

[0054] [Table 2]

[0055] 2.2. Predictors of the therapeutic effect of pembrolizumab After pembrolizumab administration, among all patients, 7 (13.0%) achieved a complete response (CR), 8 (14.8%) achieved a partial response (PR), 12 (22.2%) achieved stable disease (SD), and 21 (38.9%) experienced disease progression (PD). The overall response rate (ORR) was 31.3%. No significant differences were observed in individual factors between the pembrolizumab monotherapy group and the chemotherapy combination group (Tables 3 and 4).

[0056] [Table 3]

[0057] [Table 4]

[0058] Next, the inventors investigated the correlation between each biomarker and the therapeutic effect of pembrolizumab. Specifically, the objective response rate (ORR) was evaluated for the following eight biomarkers: CRP (≤1: n = 37, 1<: n = 17), ALB (<3.5: n = 23, 3.5≦: n = 31), lymphocytes (≤1250: n = 17, 1250<: n = 37), NLR (<6.589: n = 38, 6.589≦: n = 16), mGPS (0: n = 37, 1: n = 5, 2: n = 12), imGPS (0: n = 14, 1: n = 21, 2: n = 9, 3: n = 10).

[0059] The group with lymphocyte counts of 1250 / μL or higher had a significantly better ORR compared to the group with counts below 1250 / μL (<1250 / μL: 18.6%, ≥1250 / μL: 56.3%, p = 0.0082). However, no significant difference in ORR was observed for CPR and ALB (Figure 2).

[0060] No significant difference in ORR was observed between NLR and mGPS. On the other hand, a significant difference in ORR was observed with imGPS (score 0: 57.1%, score 1: 22.2%, score 2: 12.5%, score 3: 25%) (Figure 2). These data suggest that imGPS is a useful tool for predicting the response to pembrolizumab treatment in RMHNC.

[0061] Furthermore, the inventors conducted a multivariate analysis using age, presence or absence of concomitant chemotherapy (chemo), and each element of imGPS (CRP, ALB, and lymphocyte count) as confounding factors. Only the lymphocyte count showed a significant difference (Table 5).

[0062] [Table 5]

[0063] 2.3. Prognostic markers for pembrolizumab The median overall survival (OS) for all cases was 14.5 months, and the median progression-free survival (PFS) was 3.4 months (Figure 3). No significant differences were observed when OS / PFS was examined for age, CPS, or whether chemotherapy was administered (Figure 4).

[0064] The correlation between each imGPS parameter (CRP, ALB, and lymphocyte count) and prognosis after pembrolizumab administration was examined (Figure 5). In the low CRP group (<1 mg / dL), OS and PFS were significantly better (median OS: 17.6 months vs. 7.9 months: p = 0.0023, median PFS: 6.0 months vs. 1.2 months: p = 0.0013). In the high ALB group (≧3.5 g / dL), overall survival (OS) was significantly better (median OS: 7.9 months vs. 17.6 months: p = 0.0016), and in the high lymphocyte count group (≧1250 / μL), both OS and progression-free survival (PFS) were significantly better (median OS: 11.2 months vs. NA: p = 0.0008, median PFS: 2.4 months vs. 11.0 months: p = 0.0014).

[0065] Next, we examined the correlation between each predictor (NLR, mGPS, and imGPS) and prognosis (Figure 6). No significant difference in OS was observed with respect to NLR, but the group with a low NLR (<6.589) had a better PFS (median OS: 14.9 months vs. 5.8 months: p = 0.0992, median PFS: 6.0 months vs. 1.6 months: p = 0.0295). The group with a low mGPS had a better OS and PFS (median OS: 17.6 months vs. 14.3 months vs. 6.8 months: p = 0.0034, median PFS: 6.0 months vs. 1.6 months vs. 2.3 months: p = 0.0127). Similarly, the group with lower imGPS scores had better OS and PFS (median OS: NA vs. 12.0 months vs. 11.8 months vs. 6.1 months: p = 0.0011, median PFS: 11.0 months vs. 3.9 months vs. 2.1 months vs. 2.2 months: p = 0.0049).

[0066] Multivariate analysis was performed using age, presence or absence of chemotherapy, and imGPS components as confounding factors. Significant differences were found in CRP and lymphocyte count for overall survival, and in lymphocyte count for progression-free survival (Table 6).

[0067] [Table 6]

[0068] The correlation between pembrolizumab administration and prognosis was examined separately for the pembrolizumab monotherapy group (alone) and the chemotherapy combination group (combo). Specifically, overall survival (OS) was evaluated for each group based on CRP and ALB levels, as well as lymphocyte count. The results for the pembrolizumab monotherapy group were similar to those for the overall patient group (Figures 7 and 8).

[0069] Furthermore, the prognosis was examined by dividing the patients into a pembrolizumab monotherapy group and a pembrolizumab combination therapy group. The results for the pembrolizumab monotherapy group were similar to those for the overall patient group (Figures 9 and 10). When ROC analysis was performed, imGPS showed the highest AUC value for both OS and PFS (Table 7).

[0070] [Table 7]

[0071] These results suggest that imGPS is a superior predictive marker compared to conventionally known treatment efficacy / prognosis prediction markers such as NLR and mGPS.

Claims

1. A method for predicting the therapeutic effect of cancer immunotherapy in subjects with cancer, and / or the prognosis of subjects with cancer who have received, are currently receiving, or may receive cancer immunotherapy in the future, (a) A step of obtaining the CRP reflection value, the albumin reflection value, and the lymphocyte count reflection value in the blood sample taken from the subject, (b) A step of classifying the subjects based on the reflected value of CRP, the reflected value of Alb, and the reflected value of lymphocyte count, A method by which the therapeutic effect and / or prognosis can be predicted based on the aforementioned classification.

2. The above criteria for the target group are as follows: Classification (1): When the CRP reflection value is below threshold A, and the lymphocyte count reflection value is above threshold C. Classification (2): When the CRP reflection value is below threshold A, and the lymphocyte count reflection value is less than threshold C. Classification (3): When the CRP reflection value is greater than threshold A, the albumin reflection value is greater than or equal to threshold B, and the lymphocyte count reflection value is greater than or equal to threshold C. Classification (4): When the CRP reflection value is greater than threshold A, the albumin reflection value is greater than or equal to threshold B, and the lymphocyte count reflection value is less than threshold C. Classification (5): When the CRP reflection value is greater than threshold A, the albumin reflection value is less than threshold B, and the lymphocyte count reflection value is greater than or equal to threshold C. Classification (6): When the CRP reflection value is greater than threshold A, the albumin reflection value is less than threshold B, and the lymphocyte count reflection value is less than threshold C. The method according to claim 1, classified according to the following.

3. The method according to claim 2, wherein in at least one of the pairs of classification (1) and classification (2), classification (3) and classification (4), and classification (5) and classification (6), the classification with a smaller classification number is predicted to have a higher probability of response to the cancer immunotherapy and / or a better prognosis for the subject.

4. A method for predicting the therapeutic effect of cancer immunotherapy in subjects with cancer, The following criteria: Classification (1): imGPS(Immune-modified Glasgow Prognostic Score)=0 Classification (2) or Classification (3): imGPS=1 Classification (4) or Classification (5): imGPS=2 Classification (6): imGPS=3 The process further includes the step of calculating the target imGPS according to the above, The method according to claim 2, wherein the smaller the imGPS value, the higher the likelihood of a response to cancer immunotherapy is predicted.

5. A method for predicting the prognosis of cancer patients who have received, are currently receiving, or are likely to receive cancer immunotherapy, The following criteria: Classification (1): imGPS(Immune-modified Glasgow Prognostic Score)=0 Classification (2) or Classification (3): imGPS=1 Classification (4) or Classification (5): imGPS=2 Classification (6): imGPS=3 The process further includes the step of calculating the target imGPS according to the above, The method according to claim 2, wherein a smaller imGPS value is predicted to indicate a better prognosis.

6. The aforementioned CRP-reflecting value is the serum CRP concentration. The aforementioned Alb reflection value is the serum Alb concentration, and The aforementioned value reflecting the number of lymphocytes is the absolute number of lymphocytes, The threshold A is 0.7 to 1.5 mg / dL. The threshold B is 2.5 to 5.5 g / dL, and The method according to any one of claims 1 to 5, wherein the threshold C is 800 to 1900 counts / μL.

7. The method according to any one of claims 1 to 5, wherein the cancer immunotherapy is the administration of an immune checkpoint inhibitor.

8. The method according to claim 7, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

9. The method according to any one of claims 1 to 5, wherein the subject is a subject having head and neck cancer.

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