Method for predicting therapeutic effect of combination therapy of il-6 inhibitor and chemotherapy in pancreatic cancer patient

Abstract

The present invention provides a novel means usable for predicting a therapeutic effect of a combination therapy of an IL-6 inhibitor and a chemotherapy in a pancreatic cancer patient, said means being characterized by use of blood CD8-positive effector memory T cells as a biomarker. Specifically, in order to predict a therapeutic effect of a combination therapy of an IL-6 inhibitor and a chemotherapy in a pancreatic cancer patient, (i) the level of CD8-positive effector memory T cells that are contained in a blood sample which is collected from the pancreatic cancer patient is measured and (ii) when the level of the CD8-positive effector memory T cells is high, it is determined that the therapeutic effect yielded by the combination therapy is high.

Description

Method for predicting therapeutic effect of combination therapy of IL-6 inhibitor and chemotherapy in pancreatic cancer patients

[0001] The present invention relates to a blood biomarker that correlates with the therapeutic effect of a given combination therapy in pancreatic cancer patients. More specifically, the present invention relates to a method for predicting the prognosis of pancreatic cancer treatment by a combination therapy combining an interleukin (IL)-6 inhibitor with a chemotherapeutic agent, using blood CD8-positive effector memory T cells as an indicator, or a companion or complementary diagnostic for said treatment.

[0002] Companion diagnostics are tests conducted to determine whether a therapeutic drug will be effective for a patient before treatment. Companion diagnostics can determine whether a specific therapeutic drug is appropriate, further enhancing the efficacy and safety of treatment using that drug. In Japan, companion diagnostic products are approved as in vitro diagnostics or medical devices (companion diagnostics, etc.) that can be used to determine the appropriateness of a specific drug. The Pharmaceuticals and Medical Devices Agency (PMDA) defines "companion diagnostics, etc." as in vitro diagnostics or medical devices used to identify patients for whom a specific drug is expected to be effective and safe based on the results of biomarker analysis, but which are essential for the use of that drug. A similar term, complementary diagnostics, differs from companion diagnostics in that while they ensure the efficacy and safety of a drug, they are not essential for administering the drug. Companion diagnostics include in vitro diagnostics (companion diagnostics) and diagnostic methods used to determine the suitability of a specific therapeutic or treatment drug, kits containing companion diagnostics (and complementary diagnostics, if necessary), medical devices containing companion diagnostics (and complementary diagnostics, if necessary) or kits, or systems that combine these with software.

[0003] Pancreatic cancer is a cancer that develops in the pancreas, and most cases arise from cells in the pancreatic duct. Surgical resection is the only treatment that offers the potential for a cure, with stage I and II cancers considered resectable. However, at the time of discovery, most patients have advanced, unresectable disease, and even if resection is possible, the recurrence rate is high and the prognosis is extremely poor (Non-Patent Document 7).

[0004] For unresectable pancreatic cancer, treatment methods are determined based on whether the cancer is locally advanced, has distant metastasis, or has recurred after surgery. Locally advanced pancreatic cancer is one that cannot be removed due to factors such as cancer cell infiltration into major blood vessels, and is treated with chemotherapy or chemoradiotherapy. Chemoradiotherapy is a treatment that combines anticancer drugs with radiation therapy.

[0005] Chemotherapy is performed for pancreatic cancer with distant metastasis and / or recurrent pancreatic cancer after surgery. The current major standard chemotherapy treatments for pancreatic cancer include the following: Gemcitabine + nab-paclitaxel combination therapy (GN therapy): This treatment combines two types of intravenous anticancer drugs, administered once a week for three consecutive weeks with a break on the fourth week. This cycle is repeated every four weeks. FOLFIRINOX therapy (fluorouracil, levofolinate, irinotecan, oxaliplatin): This treatment combines multiple types of intravenous anticancer drugs, requiring two days of infusion. It is intended for patients in good general condition. Gemcitabine therapy: This intravenous anticancer drug treatment is administered once a week for three consecutive weeks with a break on the fourth week. This cycle is repeated every four weeks. S-1 therapy: This oral anticancer drug treatment has been shown to be as effective as gemcitabine therapy alone in unresectable pancreatic cancer. S-1 monotherapy is also used as adjuvant chemotherapy after surgery. ・Fluorouracil-levofolinate-nanoliposomal irinotecan therapy: A combination of multiple intravenous anticancer drugs. It is usually used as second-line chemotherapy for patients who have failed first-line gemcitabine-based chemotherapy. ・Gemcitabine-S-1 therapy: A combination of intravenous and oral anticancer drugs. It is used as preoperative chemotherapy for resectable pancreatic cancer.

[0006] Depending on the condition of each individual patient and if deemed appropriate by specific tests (including companion diagnostics), molecular targeted drugs such as olaparib and immune checkpoint inhibitors such as pembrolizumab (anti-PD-1 antibody) may also be used.

[0007] Cancer treatment is accompanied by many side effects, and it has been reported that these side effects become more severe in patients with severe symptoms such as weight loss (Non-Patent Document 11). Many studies and clinical trials are being conducted with the aim of establishing further improved treatment methods.

[0008] Inflammation mediated by JAK / STAT signaling is one of the causes of cancer chemotherapy resistance. The JAK / STAT3 pathway is activated by stimulation with multiple cytokines and growth factors, including the IL-6 family. Blockade of the IL-6 receptor in mice using an anti-IL-6 receptor antibody inhibited STAT3 activation, suggesting improved efficacy of chemotherapy for pancreatic ductal adenocarcinoma (PDAC) (Non-Patent Document 6).

[0009] Non-clinical trials, phase I clinical trials, and translational research have been conducted on combination therapy of anti-IL-6 receptor antibody (tocilizumab: TCZ) and gemcitabine-nab-paclitaxel (GN) for metastatic pancreatic cancer refractory to GN therapy, and it has been suggested that this therapy has a certain antitumor effect (Non-patent document 5).

[0010] The combined use of a JAK1 / 2 inhibitor and an IL-6 inhibitor can reduce the dose of GN therapy. The standard therapy is gemcitabine 1000 mg / m 2 Nab-paclitaxel 125 mg / m 2 The same dosing regimen was used, but with a reduced dose of gemcitabine 750 mg / m 2 + nab-paclitaxel 100 mg / m 2 is also acceptable (Non-Patent Documents 5 and 10).

[0011] T cells, a type of lymphocyte, are components of the adaptive immune system and play an important role in immune defense against tumors. DP thymocytes, precursors of T cells, express both CD4 and CD8 cell surface markers (CD4+CD8+). Differentiated and mature T cells are broadly classified as CD4+ T cells or CD8+ T cells based on the CD4 and CD8 expression patterns. CD4+ T cells are classified into Th1, Th2, Th9, Th17, Treg, and Tfh cells. Among helper T cells (Th), Th1 cells play a particularly important role in antitumor responses. Treg (regulatory T cells), immunosuppressive cells, are involved in immune tolerance to avoid self-attack, but also contribute to immune escape by cancer cells, suppressing antitumor immune responses. CD8+ T cells activated by helper T cells are also called cytotoxic T lymphocytes (CTLs), cytotoxic T cells, or killer T cells.

[0012] Figure 1 shows an illustration of CD8+ T cell differentiation after antigen presentation (Non-Patent Document 4: Ando. IMMUNOLOGICAL MEDICINE 2020, VOL. 43, NO. 1, 1-9). CD8+ T cells (naive T cells) that have never encountered an antigen are activated by antigen stimulation. Activated T cells (effector T cells: TE) undergo clonogenic proliferation, become CTLs, and attack virus-infected cells and tumor cells before dying by apoptosis. A subset of antigen-stimulated T cells differentiates into memory T cells (Tm) and resides in the body for a long time, maintaining immunological memory. Memory T cells are classified into subsets: stem cell memory T cells (TSCM), central memory T cells (TCM) that circulate in secondary lymphoid tissues, effector memory T cells (TEM) that circulate in non-lymphoid tissues, and non-circulating tissue-resident memory T cells (TRM).

[0013] Generally, cancer therapy does not have the same effect on all patients; some patients respond better than others. Many studies have been conducted on genes related to therapy to find markers of response to therapy that can determine whether a particular therapy is effective. Furthermore, some studies, although still limited, have focused on the T cell repertoire in organs and circulation.

[0014] In patients with pancreatic ductal adenocarcinoma (PDAC), responders to FOLFIRINOX therapy as neoadjuvant chemotherapy (chemotherapy administered before surgical resection of cancer) had a decrease in Treg cells in the blood and an increase in effector T cells (Non-patent literature 1: Clin Cancer Res 2021;27:6761-71, Neoadjuvant FOLFIRINOX Therapy Is Associated with Increased Effector T Cells and Reduced Suppressor Cells in Patients with Pancreatic Cancer).

[0015] In ovarian cancer patients, high levels of CD8+ effector memory T cells in ascites were associated with a good prognosis (Non-Patent Document 2: Lieber S, et al. (2018), OncoImmunology 2018, 7:5, e1424672, Prognosis of ovarian cancer is associated with effector memory CD8CT cell accumulation in ascites, CXCL9 levels, and activation-triggered signal transduction in T cells).

[0016] In melanoma patients, high levels of CD8-positive effector memory T cells in the blood have been associated with favorable treatment outcomes (Non-Patent Document 3: Oncotarget, 2017, Vol. 8, (No. 13), pp: 21539-21553, Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma).

[0017] In head and neck squamous cell carcinoma (HNSCC), the proportion of specific peripheral blood memory T cells (CD8+ CCR7+) has been reported to be associated with prognosis and cachexia (Non-Patent Document 8: Clin Cancer Res; 19(4); 889-99; Non-Patent Document 9: Journal of Cachexia, Sarcopenia and Muscle 2019; 10: 827-843).

[0018] However, there have been no reports to date examining the clinical significance of CD8-positive effector memory T cells in pancreatic cancer patients. The disclosure of the aforementioned Non-Patent Document 1 is about effector T cells, not about effector memory T cells. Furthermore, the relationship between blood markers and anti-cancer and / or anti-cachexia in pancreatic cancer has not been known. Cachexia is a metabolic disorder frequently observed in pancreatic cancer and indicates a poor treatment outcome. Furthermore, no methods have been reported to date for detecting or predicting the therapeutic effect of combination therapy of IL-6 inhibitors and chemotherapy in pancreatic cancer patients, nor has the role of T cell subsets in determining the appropriateness of pancreatic cancer treatments, including the administration of IL-6 inhibitors.

[0019] Clin Cancer Res 2021;27:6761-71, Neoadjuvant FOLFIRINOX Therapy is Associated with Increased Effector T Cells and Reduced Suppressor Cells in Patients with Pancreatic CancerLieber S, et al. (2018), OncoImmunology 2018, 7:5, e1424672, Prognosis of ovarian cancer is associated with effector memory CD8C T cell accumulation in ascites, CXCL9 levels and activation-triggered signal transduction in T cellsOncotarget, 2017, Vol. 8, (No. 13), pp: 21539-21553, Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma:Ando. IMMUNOLOGICAL MEDICINE 2020, VOL. 43, NO. 1, 1-9Mitsunaga S. et al. (2023) Fibroblast inhibition by tocilizumab enabled gemcitabine / nab-paclitaxel rechallenge for pancreatic cancer, Cancer Science, 114: 4006-4019Kristen B. Long et al.(2017) IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma, Mol Cancer Ther; 16(9), 1898-1908Lancet, 2011 Aug 13;378(9791):607-620Czystowska M, et. al., The Immune Signature of CD8+CCR7+T Cells in the Peripheral Circulation Associates with Disease Recurrence in Patients with HNSCC, Clin Cancer Res (2013) 19 (4): 889-899A. Narsale, et al., Cancer-driven changes link T cell frequency to muscle strength in people with cancer: a pilot study, Journal of Cachexia, Sarcopenia and Muscle 2019; 10: 827-843Bauer TM, et al. A Phase Ib study of ruxolitinib + gemcitabine ± nab-paclitaxel in patients with advanced solid tumors, Onco Targets Ther 2018; 11: 2399-407Mitsunaga S, et al. Supportive Care in Cancer (2020) 28:5271-5279.

[0020] An object of the present invention is to provide a means for making it possible to predict the effect of combined chemotherapy and IL-6 inhibitor treatment in pancreatic cancer patients both before and during treatment.

[0021] The present inventors investigated the relationship between the clinical efficacy of gemcitabine + nab-paclitaxel + IL-6 inhibitor combination therapy and T cell subsets, and found that the combination therapy was effective in treating advanced pancreatic cancer and improved the symptoms of cachexia in patients with high levels of CD8+ effector memory T cells in the blood.

[0022] In clinical trials, the inventors measured the amount of T cells in patient blood samples. Patients whose tumors shrank in response to combination therapy had a higher proportion of CD8+ effector memory T cells among blood T cell subsets than patients whose tumors were refractory to combination therapy, but no such correlation was observed for other subsets. Furthermore, pancreatic cancer patients with a higher proportion of CD8+ effector memory T cells also had reduced symptoms of cachexia (weight loss, nausea, and gait disturbances).

[0023] Therefore, blood CD8+ effector memory T cells may be a biomarker for predicting the efficacy of combination therapy with IL-6 inhibitors and chemotherapy and for assessing cachexia in pancreatic cancer patients. Furthermore, blood CD8+ effector memory T cells may be used as a biomarker for pre-selecting patients for treatment, i.e., for companion or complementary diagnostics.

[0024] Based on these findings, the present inventors established a minimally invasive means for predicting the therapeutic effect of a predetermined combination therapy in pancreatic cancer patients, thereby completing the following inventions: (A) Use of blood CD8-positive effector memory T cells as a biomarker for predicting the therapeutic effect of combination therapy of an IL-6 inhibitor and chemotherapy in pancreatic cancer patients. (B) A method for predicting the therapeutic effect of combination therapy of an IL-6 inhibitor and chemotherapy in pancreatic cancer patients, using the level of blood CD8-positive effector memory T cells as an indicator. (C) A combination of an IL-6 inhibitor and a chemotherapeutic agent to be administered to pancreatic cancer patients determined to be likely to respond to combination therapy of an IL-6 inhibitor and chemotherapy, using the level of blood CD8-positive effector memory T cells as an indicator. (D) A method for selecting pancreatic cancer patients for combination therapy of an IL-6 inhibitor and chemotherapy, using the level of blood CD8-positive effector memory T cells as an indicator. (E) A method for treating pancreatic cancer patients with a combination therapy of an IL-6 inhibitor and chemotherapy, which is administered to pancreatic cancer patients who have been determined to be likely to benefit from the combination therapy of an IL-6 inhibitor and chemotherapy using the level of blood CD8-positive effector memory T cells as an indicator. (F) A kit for predicting the efficacy of a combination therapy of an IL-6 inhibitor and chemotherapy or for selecting patients who are likely to benefit from the combination therapy, which kit comprises an antibody capable of identifying CD8-positive effector memory T cells.

[0025] These inventions can be specifically expressed as follows: (A1) Use of blood CD8-positive effector memory T cells as a biomarker for predicting the therapeutic effect of combination therapy of an IL-6 inhibitor and chemotherapy in pancreatic cancer patients, wherein the amount of CD8-positive effector memory T cells contained in a patient's blood sample serves as an index for predicting the therapeutic effect.

[0026] (A2) The aforementioned use, wherein the chemotherapy is gemcitabine-based chemotherapy, for example, GN therapy. (A3) The aforementioned use, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody, for example, an anti-IL-6 receptor humanized antibody or an anti-IL-6 receptor human antibody.

[0027] (A4) The use, wherein the amount of CD8-positive effector memory T cells is expressed as a ratio to the number of CD8-positive T cells, i.e., expressed as a ratio of the number of CD8-positive effector memory T cells or a measurement value that is an indicator of the number of CD8-positive T cells or a measurement value that is an indicator of the number of CD8-positive T cells.

[0028] (B1) A method for predicting the therapeutic effect of a combination therapy of an IL-6 inhibitor and chemotherapy in a pancreatic cancer patient, the method comprising: (i) quantifying the level of CD8-positive effector memory T cells contained in a blood sample collected from the pancreatic cancer patient; and (ii) indicating that the therapeutic effect of the combination therapy is high when the level of CD8-positive effector memory T cells in the patient's blood sample is high.

[0029] (B2) The method as described above, wherein the chemotherapy is gemcitabine-based chemotherapy, for example, GN therapy, or (B3) the method as described above, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody, for example, an anti-IL-6 receptor humanized antibody or an anti-IL-6 receptor human antibody.

[0030] (B4) The method, wherein the level of CD8-positive effector memory T cells is expressed as a ratio to the number of CD8-positive T cells, i.e., expressed as a ratio of the number of CD8-positive effector memory T cells or a measured value that is an indicator of the number of CD8-positive T cells or a measured value that is an indicator of the number of CD8-positive T cells in a blood sample of the patient.

[0031] (B5) The method, wherein a high level of CD8-positive effector memory T cells in the patient's blood sample compared to a predetermined reference level, for example, a ratio of 30% or more, indicates a high therapeutic effect of the combination therapy. (B6) The method, wherein a high therapeutic effect includes an improved tumor shrinkage rate or alleviation of cachexia symptoms.

[0032] (C1) A therapeutic agent comprising a combination of an IL-6 inhibitor and a chemotherapeutic agent, to be administered to a pancreatic cancer patient who has been determined to have a high therapeutic effect from a combination therapy of an IL-6 inhibitor and chemotherapy, using the level of blood CD8-positive effector memory T cells as an indicator.

[0033] (C2) An IL-6 inhibitor to be administered in combination with a chemotherapy agent to a pancreatic cancer patient who has been determined to have a high therapeutic effect from a combination therapy of an IL-6 inhibitor and chemotherapy, using the level of blood CD8-positive effector memory T cells as an indicator.

[0034] (C3) The therapeutic agent or IL-6 inhibitor, wherein the chemotherapy is gemcitabine-based chemotherapy, for example, GN therapy. (C4) The therapeutic agent or IL-6 inhibitor, wherein the level of CD8-positive effector memory T cells is expressed as a percentage of the number of CD8-positive T cells, i.e., expressed as a ratio of the number of CD8-positive effector memory T cells or a measured value that is an indicator of the number of CD8-positive T cells in a blood sample of the patient or a measured value that is an indicator of the number of CD8-positive T cells.

[0035] (C5) The therapeutic agent or IL-6 inhibitor, wherein the therapeutic effect is determined to be high when the level of CD8-positive effector memory T cells in the patient's blood is high compared to a predetermined reference level, for example, when the proportion is 30% or higher.

[0036] (C6) The therapeutic agent or IL-6 inhibitor, wherein the high therapeutic effect includes an improvement in the tumor shrinkage rate or alleviation of cachexia symptoms. (C7) A pharmaceutical containing an IL-6 inhibitor intended for administration to a pancreatic cancer patient determined to have a high therapeutic effect from a combination therapy of an IL-6 inhibitor and chemotherapy, wherein the patient is determined to have a high therapeutic effect if the ratio of the amount of CD8-positive effector memory T cells to the amount of CD8-positive T cells in the peripheral blood is 30% or more, and the pharmaceutical containing an IL-6 inhibitor is to be administered to the patient in combination with a chemotherapeutic agent.

[0037] (C8) The therapeutic agent or the IL-6 inhibitor or the medicine containing the IL-6 inhibitor, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody, for example, an anti-IL-6 receptor humanized antibody or an anti-IL-6 receptor human antibody.

[0038] (D1) A method for selecting a pancreatic cancer patient as a target for combination therapy with an IL-6 inhibitor and chemotherapy, the method comprising: measuring the level of CD8-positive effector memory T cells in a blood sample from the patient; and determining the patient as a target for combination therapy with an IL-6 inhibitor and chemotherapy when the level of CD8-positive effector memory T cells in the blood sample from the patient is high.

[0039] (D2) The method as described above, wherein the chemotherapy is gemcitabine-based chemotherapy, for example, GN therapy. (D3) The method as described above, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody, for example, an anti-IL-6 receptor humanized antibody or an anti-IL-6 receptor human antibody.

[0040] (D4) The method, wherein the level of CD8-positive effector memory T cells is expressed as a ratio to the number of CD8-positive T cells, i.e., expressed as a ratio of the number of CD8-positive effector memory T cells or a measured value that is an indicator of the number of CD8-positive T cells or a measured value that is an indicator of the number of CD8-positive T cells in a blood sample of the patient.

[0041] (D5) The method, wherein the patient is determined to be a subject to combination therapy with an IL-6 inhibitor and chemotherapy when the level of CD8-positive effector memory T cells in the patient's blood sample is higher than a predetermined reference level, for example, when the proportion is 30% or higher.

[0042] (E1) A method for treating a patient with pancreatic cancer, comprising: (i) measuring the level of CD8-positive effector memory T cells contained in a blood sample from the patient; (ii) indicating that the therapeutic effect of the combination therapy is high when the level of CD8-positive effector memory T cells in the blood sample from the patient is high; and (iii) administering a combination therapy of an IL-6 inhibitor and chemotherapy to a patient with pancreatic cancer for whom the therapeutic effect of the combination therapy is indicated to be high.

[0043] (E2) The method as described above, wherein the chemotherapy is gemcitabine-based chemotherapy, for example, GN therapy. (E3) The method as described above, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody, for example, an anti-IL-6 receptor humanized antibody or an anti-IL-6 receptor human antibody.

[0044] (E4) The method, wherein the level of CD8-positive effector memory T cells is expressed as a ratio to the number of CD8-positive T cells, i.e., expressed as a ratio of the number of CD8-positive effector memory T cells or a measured value that is an indicator of the number of CD8-positive T cells or a measured value that is an indicator of the number of CD8-positive T cells in the patient's blood sample ... effector memory T cells.

[0045] (E5) The method, wherein a high level of CD8-positive effector memory T cell count in the patient's blood sample compared to a predetermined reference level, for example, a rate of 30% or higher, indicates a high therapeutic effect of the combination therapy.

[0046] (E6) The method, wherein the high therapeutic effect includes an improvement in tumor shrinkage rate or alleviation of cachexia symptoms. (F1) A kit used for predicting the effect of a combination therapy of an IL-6 inhibitor and chemotherapy or for selecting patients who are expected to benefit from the combination therapy, the kit comprising an antibody capable of identifying CD8-positive effector memory T cells.

[0047] (F2) The above kit, wherein an antibody capable of identifying CD8-positive effector memory T cells is used to measure the amount of CD8-positive effector memory T cells contained in a blood sample from a pancreatic cancer patient.

[0048] (F3) The above kit, wherein the chemotherapy is gemcitabine-based chemotherapy, for example, GN therapy. (F4) The above kit, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody, for example, an anti-IL-6 receptor humanized antibody or an anti-IL-6 receptor human antibody.

[0049] (F5) The kit further comprises a plurality of antibodies capable of identifying CD8-positive effector memory T cells, for example, five or more types of antibodies including, but not limited to, an anti-CD3 antibody, a CD56 antibody, an anti-CD8 antibody, an anti-CCR7 antibody, and an anti-CD45RA antibody or an anti-CD45RO antibody. The types of antibodies may be other than those mentioned above, as long as they can identify CD8-positive effector memory T cells.

[0050] Cancer treatments are associated with many side effects, and it has been reported that these side effects are more severe in patients with severe symptoms such as weight loss (Non-Patent Document 11: Mitsunaga S, et al. Supportive Care in Cancer 2020). Therefore, in order to quickly and accurately select a therapy that achieves the best results for the patient and minimize side effects, it is necessary to minimize patient symptoms, such as gastrointestinal symptoms that contribute to weight loss. Adding an IL-6 inhibitor to chemotherapy with GN2 (gemcitabine + nab-paclitaxel), the current standard treatment for pancreatic cancer, may be expected to have a therapeutic effect of reducing gastrointestinal symptoms.

[0051] The present invention provides a means for effectively administering such combination therapy using a minimally invasive blood biomarker, making it possible to identify pancreatic cancer patients who will respond or are likely to respond to combination therapy involving inhibition of the IL-6 signaling pathway, using the amount of CD8+ effector memory T cells in the blood as an indicator.

[0052] As previously mentioned, it has been reported that the peripheral blood memory T cell fraction is associated with prognosis and cachexia in head and neck squamous cell carcinoma (HNSCC) (Non-Patent Documents 8 and 9). Recently, the present inventors have successfully identified a T cell fraction associated with a favorable clinical course and found that among peripheral blood memory T cell fractions, CD8+ effector memory T cells are associated with pancreatic cancer treatment outcomes and cachexia. Cachexia is a metabolic disorder frequently observed in pancreatic cancer and indicates a state of poor treatment outcome. These findings suggest that measuring the peripheral blood fraction of CD8+ effector memory T cells may be able to predict the overall clinical course.

[0053] Differentiation of CD8+ T cells after antigen presentation. Gating strategy for blood CD8+ effector memory T cells (patient ID GAP01). Volcano plot showing the correlation between specific immune cell populations and combination therapy. Amount of CD8+ effector memory T cells and anti-tumor effect. The amount of CD8+ effector memory T cells is expressed as the ratio of the number of CD8+ effector memory T cells to the total number of CD8+ T cells (vertical axis %). Comparison of the proportion of CD8+ effector memory T cells between responder and non-responder groups. Comparison of the proportion of other blood T cell subsets between responder and non-responder groups. Correlation between the proportion of CD8+ effector memory T cells and symptoms of cachexia.

[0054] The present invention is described in detail below. The present invention relates to a marker for assessing or predicting the therapeutic effect of pancreatic cancer treatment using a combination therapy of an IL-6 inhibitor and chemotherapy. In this invention, the level of CD8-positive effector memory T cells in the blood of pancreatic cancer patients is used as an indicator to predict or assess the therapeutic effect of pancreatic cancer and the suitability of the treatment. The present invention further relates to a method for treating pancreatic cancer patients by selecting those pancreatic cancer patients who are predicted or detected to have a high therapeutic effect and administering a combination of an IL-6 inhibitor and a chemotherapeutic agent.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In carrying out the present invention, any methods and materials similar or equivalent to those described herein can be used, but the preferred methods and materials are described herein. All publications mentioned herein are incorporated by reference.

[0056] In the present invention, prediction of therapeutic effect can be rephrased as prediction of prognosis, judgment of suitability of treatment, detection of therapeutic effect, judgment of therapeutic effect, diagnosis of therapeutic effect, etc. Furthermore, in the present invention, the expressions "shown to have a high therapeutic effect" or "predicted to have a high therapeutic effect" can be rephrased as "determined to have a high therapeutic effect" or "detected to have a high therapeutic effect", etc.

[0057] Furthermore, in the present invention, a "pancreatic cancer patient predicted to benefit from a high therapeutic effect" can be rephrased as a "patient suitable for pancreatic cancer treatment" using a combination therapy of an IL-6 inhibitor and chemotherapy, or a "responsive patient" or "responder" to the combination therapy.

[0058] In the present invention, "blood CD8-positive effector memory T cells" may be referred to as "biomarker," "marker," "blood marker," etc. A "test sample" or "patient blood sample" refers to a blood sample obtained from a patient who is a subject to be tested for pancreatic cancer in the present invention. Thus, the present invention can include a step of collecting a blood sample from a patient to obtain such a sample.

[0059] Suitable patients for the present invention are those with advanced pancreatic cancer that is unresectable and refractory to standard chemotherapy. Advanced pancreatic cancer may be either locally advanced pancreatic cancer or distant metastatic pancreatic cancer. Pancreatic cancer may be untreated advanced pancreatic cancer or previously treated pancreatic cancer that has recurred.

[0060] The terms "resistant," "refractory," and "resistant" are used interchangeably and refer to a state in which a cell or individual is unresponsive (also referred to as sensitive) to disease treatment or therapy and / or has a reduced ability to generate a significant response. For example, a pancreatic cancer resistant to a chemotherapeutic agent is a pancreatic cancer that shows no response to chemotherapy or does not show a significant response, such as a partial or complete response, to treatment with chemotherapy. Administration of a drug to a pancreatic cancer that is "resistant" or "refractory" to a drug not only fails to produce the desired effect, but may even lead to further progression or transformation into a more aggressive pancreatic cancer. In one embodiment, resistance (refractory) of pancreatic cancer to a chemotherapeutic agent may be assessed based on the presence or absence of markers, such as genes, proteins, or histological features, specifically expressed in such resistant cancers, in cancer tissue collected before treatment. In the present invention, "resistance" or "refractory" may refer to either "innate resistance" or "acquired resistance."

[0061] The term "intrinsic resistance" refers to the innate insensitivity of cells or individuals to drugs. When cells or individuals have innate resistance to a drug, the drug is ineffective or less effective than when there is no resistance (i.e., when the cells or individuals are sensitive or responsive). No drug treatment achieves 100% effectiveness, and there will always be people for whom the drug does not work, or non-responders. It is said that the effectiveness rate of pharmaceuticals for many diseases, including cancer, is generally around several tens of percent.

[0062] The term "acquired resistance" refers to a state in which a cell or an individual, despite being naturally responsive (or sensitive) to a drug, subsequently acquires a resistance to that drug through exposure. Acquired resistance results in a state in which a drug that was initially effective becomes ineffective during administration or becomes less effective than in the absence of resistance (i.e., responsiveness). In particular, acquired resistance in the present invention may be resistance that develops after conventional treatment. For example, antiangiogenic therapeutic agents are commonly used in many cancer treatments, but even if they are effective initially, repeated treatments can eventually lead to the acquisition of resistance. Pancreatic cancer that is resistant to a chemotherapeutic agent may no longer regress or even progress in the presence of the chemotherapeutic agent.

[0063] The term "recurrence" refers to the reappearance or growth of cancer after it has been cured or shrunk by treatment. Even when treatment appears successful, small, invisible tumors that were not completely removed by surgery may reappear, or tumors that were shrunk by chemotherapy or radiation therapy may grow again. Recurrence can occur when the same cancer reappears in the same location or near the original site, or in a different organ or tissue. The reappearance of the same cancer in a different organ or tissue from the original site is specifically called "metastasis." Cancer cells enter the bloodstream or lymphatic system from the site of initial development and travel via the bloodstream or lymphatic system to other organs, where they grow. Cancer often metastasizes to areas with abundant blood supply, such as lymph nodes, lungs, liver, brain, and bones. In the case of cancer that recurs, individuals with the cancer have undergone conventional treatment, such as chemotherapy or radiation therapy. Therefore, cancer that recurs may be cancer with acquired resistance to conventional treatment.

[0064] The treatment for pancreatic cancer in the present invention combines the administration of an IL-6 inhibitor with chemotherapy, a standard therapy for pancreatic cancer. Chemotherapy, a standard therapy for pancreatic cancer, includes, but is not limited to, GN therapy (a combination of gemcitabine hydrochloride and nab-paclitaxel). Herein, gemcitabine hydrochloride may also be referred to as GEM, and nab-paclitaxel may also be referred to as nab-PTX.

[0065] In one embodiment, the chemotherapeutic agent used in the standard therapy is gemcitabine or a pharmaceutically acceptable salt thereof (e.g., gemcitabine hydrochloride). In another embodiment, the chemotherapeutic agent used in the standard therapy is gemcitabine or a pharmaceutically acceptable salt thereof (e.g., gemcitabine hydrochloride) and nanoparticles comprising albumin and a taxane (e.g., nab-paclitaxel (Abraxane)). （登録商標） In this specification, standard therapy involving administration of gemcitabine or a pharmaceutically acceptable salt thereof may be referred to as "gemcitabine-based chemotherapy."

[0066] Chemotherapy in combination with administration of an IL-6 inhibitor may be a chemotherapy that will become a standard therapy for pancreatic cancer in the future. Detailed information about such chemotherapeutic agents is available from sources that are easily accessible to experts, such as the websites of the FDA in the United States and the PMDA in Japan, and published materials from related academic societies.

[0067] In one aspect, the pancreatic cancer treatment of the present invention can reduce the dose of the chemotherapeutic agent used in standard therapy by administering an IL-6 inhibitor in combination with the chemotherapeutic agent used in standard therapy. For example, the current standard therapy of gemcitabine at 1000 mg / m 2 and nab-paclitaxel 125 mg / m 2 The dose of either or both of gemcitabine and nab-paclitaxel can be reduced from a dosing regimen of 750 mg / m 2 , nab-paclitaxel 100 mg / m 2 It can be said that:

[0068] IL-6 inhibitors, also known as IL-6 signal inhibitors, are substances that block IL-6-mediated signal transduction and inhibit the biological activity of IL-6. Specific examples of IL-6 inhibitors include substances that bind to IL-6, substances that bind to the IL-6 receptor (IL-6R), and substances that bind to gp130, an IL-6 signal transduction molecule. Further examples of IL-6 inhibitors include inhibitors of the JAK-STAT pathway and MAP kinase pathway downstream of IL-6 signaling, particularly substances that inhibit STAT3 phosphorylation, which is important in IL-6-mediated intracellular signaling, such as AG490 and ruxolitinib. IL-6 inhibitors include, but are not limited to, anti-IL-6 antibodies, anti-IL-6 receptor antibodies, anti-gp130 antibodies, modified IL-6, soluble modified IL-6 receptors, partial IL-6 peptides, partial IL-6 receptor peptides, and small molecule compounds exhibiting similar activities.

[0069] Examples of antibodies used as IL-6 inhibitors include anti-IL-6 antibodies, anti-IL-6 receptor antibodies, and anti-gp130 antibodies. The origin of the antibodies used in the present invention is not particularly limited, but is preferably mammalian, and more preferably human.

[0070] The antibodies used in the present invention can be obtained as polyclonal or monoclonal antibodies using known means. Mammalian-derived monoclonal antibodies are particularly preferred as the antibodies used in the present invention. Mammalian-derived monoclonal antibodies include those produced by hybridomas and those produced by hosts transformed with expression vectors containing antibody genes using genetic engineering techniques. The antibodies used as IL-6 inhibitors in the present invention block the intracellular transmission of the biological activity of IL-6 by binding to IL-6, IL-6 receptor, gp130, etc. Methods for obtaining mammalian-derived monoclonal antibodies are known, and a skilled artisan can appropriately perform the method with appropriate ingenuity (although not easy).

[0071] The antibody used in the present invention may be an antibody fragment or a modified antibody fragment thereof, as long as it can be suitably used in the present invention. Examples of antibody fragments include Fab, F(ab'), Fv, and single-chain Fv (scFv) in which the H chain and L chain Fv are linked via a suitable linker.

[0072] Specific examples of anti-IL-6 antibodies include, but are not limited to, MH166 (Matsuda, T. et al., Eur. J. Immunol. (1998) 18, 951-956) and SK2 antibody (Sato K et al., 21st Annual Meeting of the Japanese Society for Immunology, Academic Records (1991) 21, 166). Specific examples of anti-IL-6 receptor antibodies will be described later.

[0073] Specific examples of anti-gp130 antibodies include, but are not limited to, AM64 antibody (Japanese Patent Laid-Open Publication No. 3-219894), 4B11 antibody, 2H4 antibody (US Pat. No. US5,571,513), and B-P8 antibody (Japanese Patent Laid-Open Publication No. 8-291199).

[0074] The IL-6 variants used in the present invention are substances that have binding activity to the IL-6 receptor but do not transmit the biological activity of IL-6. That is, the IL-6 variants competitively bind to the IL-6 receptor with IL-6 but do not transmit the biological activity of IL-6, thereby blocking signal transduction by IL-6.

[0075] IL-6 variants are prepared by introducing mutations by substituting amino acid residues in the amino acid sequence of IL-6. The origin of the IL-6 from which the IL-6 variant is derived may be any; however, considering antigenicity and other factors, human IL-6 is preferred. Specifically, the secondary structure of the IL-6 amino acid sequence is predicted using a known molecular modeling program, such as WHATIF (Vriend et al., J. Mol. Graphics (1990) 8, 52-56), and the overall effect of the substituted amino acid residues is evaluated. After determining appropriate substituted amino acid residues, a gene encoding the IL-6 variant is obtained by introducing mutations to substitute amino acids using a vector containing a nucleotide sequence encoding the human IL-6 gene as a template, using a conventional PCR method. This gene can be inserted into an appropriate expression vector as needed, and the IL-6 variant can be obtained according to known methods for expressing, producing, and purifying recombinant antibodies.

[0076] Specific examples of IL-6 variants include the IL-6 variants disclosed in Brakenhoff et al., J. Biol. Chem. (1994) 269, 86-93, and Savino et al., EMBO J. (1994) 13, 1357-1367, WO96-18648, and WO96-17869.

[0077] An IL-6 receptor partial peptide is a peptide consisting of a part or all of the amino acid sequence of the region involved in the binding of IL-6 to the IL-6 receptor in the amino acid sequence of the IL-6 receptor. Such a peptide usually consists of 10 to 80, preferably 20 to 50, and more preferably 20 to 40 amino acid residues.

[0078] An IL-6 receptor partial peptide can be prepared by identifying a region in the amino acid sequence of the IL-6 receptor that is involved in the binding between IL-6 and the IL-6 receptor, and then using a commonly known method, such as genetic engineering or peptide synthesis, based on the amino acid sequence of a part or all of the identified region.

[0079] To prepare a partial peptide of IL-6 receptor by genetic engineering techniques, a DNA sequence encoding the desired peptide can be inserted into an expression vector, and the peptide can be obtained according to the above-mentioned recombinant antibody expression, production and purification methods.

[0080] To prepare an IL-6 receptor partial peptide by peptide synthesis, a method commonly used in peptide synthesis, such as solid-phase synthesis or liquid-phase synthesis, can be used. A preferred embodiment of the IL-6 inhibitor is a substance that binds to the IL-6 receptor (IL-6R), particularly an anti-IL-6 receptor antibody. Anti-IL-6 receptor antibodies approved for clinical use include monoclonal antibodies such as tocilizumab, satralizumab, and sarilumab, all of which can be used in the present invention. Herein, anti-IL-6 receptor antibodies may also be referred to as anti-IL-6R antibodies.

[0081] Tocilizumab (Actemra （登録商標） Tocilizumab (MRA, CAS No.: 375823-41-9) is a humanized anti-human IL-6 receptor monoclonal antibody of the IgG1 subclass (Ann Rheum Dis 2000; 59(suppl I):i21-i27). Tocilizumab was created using recombinant DNA technology in Chinese hamster ovary (CHO) cells, with the complementarity-determining regions (CDRs), which have particularly high affinity for antigens, converted to mouse human IL-6R monoclonal antibodies, and the remaining portions converted to human IgG1. Tocilizumab exerts its therapeutic effect by specifically binding to both soluble IL-6R and membrane-bound IL-6R and inhibiting the biological action of IL-6. Tocilizumab is the world's first IL-6 inhibitor to be put to practical use. In this specification, tocilizumab may also be referred to as TCZ.

[0082] Sarilumab (Kevzara （登録商標） , SAR153191 or REGN88) is a （登録商標） It is a fully human IgG1 monoclonal antibody that binds to the anti-IL-6 receptor and is the second most effective IL-6 inhibitor after IL-6 inhibitor IL-6.

[0083] satralizumab (Enspryng) （登録商標）, SA237, or RG6168) is a pH-dependent binding humanized anti-IL-6 receptor monoclonal antibody. Satralizumab is a humanized IgG2 antibody created by modifying its amino acid sequence using antibody engineering techniques to confer properties such as pH-dependent antigen binding, a lower antibody isoelectric point (pI), and enhanced binding to fetal Fc receptors (FcRn) under acidic conditions in order to improve blood retention. Satralizumab is also known as an anti-IL-6 receptor recycling antibody.

[0084] In one embodiment, the anti-IL-6 receptor antibody can be an antibody having the same antigen-binding properties as tocilizumab. For example, the anti-IL-6 receptor antibody can be an anti-IL-6 receptor antibody that recognizes the same epitope as that recognized by tocilizumab. The anti-IL-6 receptor antibody can be an antibody or an antigen-binding fragment thereof comprising hypervariable regions (CDRs) in the heavy and light chains of tocilizumab, each having an amino acid sequence identical to the amino acid sequence of the CDR.

[0085] An "anti-IL-6 receptor antibody that recognizes the same epitope as that recognized by tocilizumab" refers to an antibody that blocks 50% or more of the binding of tocilizumab to its own antigen in a competitive assay. Conversely, tocilizumab blocks 50% or more of the binding of an "anti-IL-6 receptor antibody that recognizes the same epitope as that recognized by tocilizumab" to its own antigen in a competitive assay.

[0086] In one aspect, the anti-IL-6 receptor antibody may be an antibody or antigen-binding fragment thereof comprising amino acids having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of tocilizumab. In one aspect, the anti-IL-6 receptor antibody may be an antibody or antigen-binding fragment thereof comprising CDRs each comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of each CDR in the heavy chain and light chain of tocilizumab. In one aspect, the anti-IL-6 receptor antibody may be an antibody or antigen-binding fragment thereof comprising a VH region and a VL region comprising amino acid sequences having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of the VH region and VL region, respectively, of tocilizumab.

[0087] The above-mentioned IL-6 inhibitors can be formulated according to conventional methods (see, for example, Remington's Pharmaceutical Sciences, latest edition, Mark Publishing Company, Easton, USA). Furthermore, pharmaceutically acceptable carriers and / or additives may also be contained, if necessary. For example, surfactants (e.g., PEG, Tween), excipients, antioxidants (e.g., ascorbic acid), colorants, flavorings, preservatives, stabilizers, buffers (e.g., phosphate, citric acid, other organic acids), chelating agents (e.g., EDTA), suspending agents, isotonicity agents, binders, disintegrants, lubricants, flow enhancers, flavoring agents, etc. However, the IL-6 inhibitors used in the present invention are not limited to these and may also contain other commonly used carriers as appropriate. Specific examples include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, cornstarch, and inorganic salts. Other low-molecular-weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulins, as well as amino acids, may also be included. To prepare an aqueous solution for injection, the IL-6 inhibitor is dissolved in an isotonic solution containing, for example, physiological saline, glucose, or other adjuvants. Examples of adjuvants include D-sorbitol, D-mannose, D-mannitol, and sodium chloride. Appropriate solubilizers, such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, PEG), and nonionic surfactants (polysorbate 80 or 20, HCO-50), may also be used in combination.

[0088] Preferably, the above-mentioned IL-6 inhibitor is formulated into a dosage form suitable for administration to cancer patients. In one embodiment, a pharmaceutical formulation that is already commercially available as an IL-6 inhibitor can be used (with an expanded indication, if necessary).

[0089] In the present invention, an IL-6 inhibitor is used in combination therapy with chemotherapy for pancreatic cancer patients selected by a companion or complementary diagnosis using blood CD8-positive effector memory T cells as an indicator. In one embodiment, administration of the IL-6 inhibitor can be performed prior to administration of the chemotherapeutic agent. In one embodiment, administration of the IL-6 inhibitor can be performed simultaneously with administration of the chemotherapeutic agent. In one embodiment, administration of the IL-6 inhibitor can be performed subsequent to administration of the chemotherapeutic agent. In one embodiment, administration of the IL-6 inhibitor and the chemotherapeutic agent is performed within one month, or within about one, two, or three weeks, or within about one, two, three, four, five, or six days of each other. Combination therapy combining an IL-6 inhibitor and chemotherapy may also be used in combination with radiation therapy.

[0090] In one embodiment, an example of a dosing regimen for a combination therapy combining an IL-6 inhibitor with chemotherapy is that mentioned in the Examples (i.e., described in Non-Patent Document 5). Still other dosing regimens can also be used.

[0091] In one aspect of the present invention, the level of CD8-positive effector memory T cells in a blood sample collected from a pancreatic cancer patient is measured. The blood sample is a sample derived from blood. The blood-derived sample is not limited as long as it contains lymphocytes, but is preferably peripheral blood or whole blood, with peripheral blood being particularly preferred. Methods for obtaining blood samples from subjects are well known to those skilled in the art.

[0092] PBMCs (Peripheral Blood Mononuclear Cells) are mononuclear cells (monocytes) including monocytes and lymphocytes isolated from peripheral blood. PBMCs contain various blood cells, including T cells (CD4+ / CD8+ cells), B cells, NK (natural killer) cells, monocytes, and various lymphocytes such as dendritic cells. Methods for obtaining PBMCs are well known to those skilled in the art. PBMCs are generally isolated and collected from fresh blood collected from humans or animals by density gradient centrifugation to remove plasma components, red blood cells, platelets, and granulocytes.

[0093] In the present invention, the terms "amount of CD8-positive effector memory T cells," "level of CD8-positive effector memory T cells," and "proportion of CD8-positive effector memory T cells" all refer to the amount of CD8-positive effector memory T cells in a blood sample. Specifically, these are expressed as a measured value or concentration that serves as an indicator of quantity, such as the number or ratio of CD8-positive effector memory T cells.

[0094] In one embodiment, the level of CD8-positive effector memory T cells can be expressed as a proportion relative to the amount of immune cells in peripheral blood (or PBMCs), e.g., as a percentage relative to the number of CD8-positive T cells (e.g., CD3-positive CD8-positive cells or CD8-positive cells), such as: number of CD3-positive CD8-positive effector memory T cells / number of CD3-positive CD8-positive cells × 100 (%); number of CD8-positive effector memory T cells / number of CD8-positive cells × 100 (%).

[0095] In one embodiment, a value indicating the amount of CD8+ effector memory T cells can be measured as mean fluorescence intensity (MFI), absorbance, or luminescence. For example, the number of CD8+ effector memory T cells (TEMs) or the expression level of a marker on immune cells, as expressed by MFI, absorbance, or luminescence, indicates the proportion of the amount of CD8+ T cells (e.g., cell number, MFI, absorbance, or luminescence). Specifically, the proportion of the number of immune cells (e.g., CD3+CD8+ cells or CD8+ cells) in peripheral blood (or PBMCs) can be expressed as, for example, CD3+CD8+ effector memory T cell MFI / CD3+CD8+ cell MFI×100(%) or CD8+ effector memory T cell MFI / CD8+ cell MFI×100(%).

[0096] CD8+ effector memory T cells are distinguished from other cells in the blood by markers, such as proteins and receptors expressed on their cell surface. Table 1 shows a list of examples of markers expressed on the cell surface of representative immune cells in peripheral blood.

[0097]

[0098] In the present invention, the method for measuring the amount of CD8-positive effector memory T cells is not particularly limited. For example, the amount of CD8-positive effector memory T cells in peripheral blood collected from a patient can be measured by flow cytometry analysis using a fluorescently labeled antibody.

[0099] Specifically, peripheral blood mononuclear cells (PBMCs) are stained with antibodies against cell membrane surface antigens and intracellular antigens, and the respective markers are measured by flow cytometry. For example, CD8+ effector memory T cells can be identified by selecting cells that are CD3+ / CD56- / CD8+ / CCR7- / CD45RA-. They can also be identified by selecting cells that are CD3+ / CD56- / CD8+ / CCR7- / CD45RO+. See, for example, Kwiecien I., et al. (2022) Effector Memory T Cells and CD45RO+ Regulatory T Cells in Metastatic vs. Non-Metastatic Lymph Nodes in Lung Cancer Patients, Front Immunol. 13: 864497.

[0100] More specifically, for example, CD45+ leukocytes are selected from PBMCs, granulocytes are removed from the leukocytes using CD15, and myeloid cells are removed using SSC-A to obtain the fraction from which CD3+ and CD56- T cells are selected. Among these, CD4+ T cells are removed, and CD3+ / CD56- / CD4- / CD8+ T cells are selected. Furthermore, CD45RA- and CCR7 (CD197)- cells are selected, thereby obtaining CD3+ / CD56- / CD8+ / CCR7- / CD45RA- CD8-positive effector memory T cells. For example, when the CD3 expression level is 4 x 10 3 or higher and CD56 expression level is 2-6 x 10 2 The following T cells were identified: CD3+ T cells and CD4 expression levels of 1×10 3and CD8 expression is 2×10 3 These T cells were classified as CD8+ T cells and those with CCR7 (CD197) expression levels of 1×10 3 and CD45RA expression is 2×10 2 The following T cells are defined as CCR7 / CD45RA double-negative cells, and according to this criterion, CD8-positive effector memory T cells with CD3+ / CD56- / CD8+ / CCR7- / CD45RA- can be identified. Furthermore, using an anti-CD45RO antibody, CD8-positive effector memory T cells with CD3+ / CD56- / CD8+ / CCR7- / CD45RO+ can be identified.

[0101] Examples of each cell antigen marker are listed below: anti-CD45 antibody (BD Biosciences, cat# 560178, etc.), anti-CD15 antibody (BD Biosciences), anti-CD3 antibody (BD Biosciences, custom), anti-CD56 antibody (BD Biosciences, cat# 564057), anti-CD8 antibody (BD Biosciences, cat# 565695), anti-CCR7 (CD197) antibody (BioLegend), and anti-CD45RA antibody (BD Biosciences, cat# 740298).

[0102] In the present invention, the amount of CD8+ effector memory T cells can also be determined by detecting CD8+ effector memory T cells using an antibody capable of distinguishing CD8+ effector memory T cells. Such antibodies are not particularly limited as long as they can recognize proteins or receptors expressed on the surface of CD8+ effector memory T cells, and examples include anti-CD3, CD56, anti-CD8, anti-CCR7, and anti-CD45RA antibodies. In the present invention, it is preferable to use a combination of five or more antibodies, including, but not limited to, these antibodies. An anti-CD45RO antibody can also be used instead of an anti-CD45RA antibody. The antibody capable of distinguishing CD8+ effector memory T cells can be a polyclonal or monoclonal antibody. Alternatively, it can be a multispecific antibody that mutually recognizes different antigenic determinants on proteins or receptors expressed on the surface of CD8+ effector memory T cells.

[0103] In one embodiment, the present invention also provides a kit for predicting the efficacy of pancreatic cancer treatment or for selecting patients who are likely to benefit from a combination therapy, the kit comprising an antibody capable of identifying CD8-positive effector memory T cells. Preferably, but not necessarily, the antibody capable of identifying CD8-positive effector memory T cells is fluorescently labeled. The kit can be used alone or in flow cytometry.

[0104] An example of the kit of the present invention is a kit for measuring the amount of CD8-positive effector memory T cells in a companion or complementary diagnosis for pancreatic cancer treatment, which kit (i) measures the amount of CD8-positive effector memory T cells contained in a blood sample collected from a pancreatic cancer patient, (ii) indicates that the therapeutic effect of the combination of an IL-6 inhibitor and chemotherapy on pancreatic cancer is high when the amount of CD8-positive effector memory T cells is high compared to a predetermined reference level, and (iii) administers combined treatment of an IL-6 inhibitor and chemotherapy to patients for whom the treatment is indicated to be highly effective.

[0105] In the present invention, the therapeutic effect of a combination of an IL-6 inhibitor and chemotherapy on pancreatic cancer is predicted using the amount of CD8-positive effector memory T cells as an indicator. A high amount of CD8-positive effector memory T cells indicates a high therapeutic effect of a combination of an IL-6 inhibitor and chemotherapy on pancreatic cancer.

[0106] In the present invention, the phrase "the combined use of an IL-6 inhibitor and chemotherapy has a high therapeutic effect on pancreatic cancer" refers to a case in which at least one of the following desirable therapeutic effects can be achieved: - Reduction in the number of cancer cells - Reduction in tumor size - Reduction in the rate of cancer cell infiltration into peripheral organs - Reduction in tumor metastasis or tumor growth rate - Alleviation of cachexia symptoms.

[0107] The therapeutic effect, i.e., efficacy, of treatment for pancreatic cancer can be evaluated using known general methods and indicators. For example, with regard to tumor growth inhibition, according to the National Cancer Institute (NCI) criteria, a T / C of 42% or less is the minimum level of antitumor activity. A T / C of <10% is considered a high level of antitumor activity, and T / C (%) = median tumor volume of treated subjects / median tumor volume of control subjects × 100.

[0108] In one embodiment, the therapeutic effect of a cancer treatment, i.e., the effectiveness of the anticancer effect, can be evaluated using known indicators related to the condition of the patient, the affected organ, or the affected cells. Common indicators include, for example, the "response rate," which indicates the percentage of patients whose cancer cells shrink or disappear after a certain cancer treatment. Another example is the "disease control rate (DCR)," which is the response rate, which is the sum of CR (complete response) and PR (partial response), plus SD (stable disease), which indicates no change in tumor size. Other examples include partial response (PR), complete response (CR), overall response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), pathological complete response (pCR), and clinical complete response (cCR).

[0109] ORR refers to the proportion of patients who experience a reduction in the size or volume of cancer for a minimum period of time, and can be expressed as the sum of the complete response rate and partial response rate. DCR refers to the proportion of patients whose disease does not progress and can be expressed as the sum of the complete response rate, partial response rate, and stable disease rate (SD). PFS, also known as "time to tumor progression," indicates the length of time during and after treatment during which a patient survives without cancer progression, including the time during which a patient experiences CR or PR, as well as the time during which a patient experiences SD. DFS refers to the length of time during and after treatment during which a patient survives without recurrence or other disease. OS refers to the length of time a subject survives from the start of treatment. The extension of OS due to treatment refers, for example, to the extension of the point estimate of the median survival time from the start of the study in a group of treated patients compared to a group of untreated patients. The "group" mentioned above refers to a collection of individuals who require cancer treatment, i.e., a "patient population."

[0110] In one embodiment, efficacy (therapeutic effect) for treating pancreatic cancer is any of PR, CR, PFS, DFS, ORR, DCR, or OS as assessed using Fixed Response Evaluation Criteria in Cancer (RECIST) 1.1 response criteria.

[0111] In the present invention, blood CD8-positive effector memory T cells are used as a biomarker for predicting the therapeutic effect of combination therapy of an IL-6 inhibitor and chemotherapy in pancreatic cancer patients. The present invention makes it possible to predict the effect of combination therapy of an IL-6 inhibitor and chemotherapy and evaluate cachexia in pancreatic cancer patients not only before but also during treatment. Specifically, to predict the therapeutic effect of combination therapy of an IL-6 inhibitor and chemotherapy in pancreatic cancer patients, (i) the amount or proportion of CD8-positive effector memory T cells in a blood sample collected from the pancreatic cancer patient is measured, and (ii) a high amount, level, or proportion of CD8-positive effector memory T cells is determined to be a high therapeutic effect of the combination therapy.

[0112] In the present invention, "high amount of CD8+ effector memory T cells" or "high level of CD8+ effector memory T cells" refers to a high number or a high proportion of CD8+ effector memory T cells compared to an appropriate reference level. For example, a combination therapy is considered to be highly effective when the level of CD8+ effector memory T cells contained in a blood sample from a pancreatic cancer patient (i.e., a subject) is high compared to a predetermined reference level. For example, the reference level can be the average level of CD8+ effector memory T cells in a group of pancreatic cancer patients refractory to combination therapy of an IL-6 inhibitor and chemotherapy. Specifically, a "high amount of CD8+ effector memory T cells" or "high level of CD8+ effector memory T cells" can be stated when the amount of CD8+ effector memory T cells contained in a blood sample from a subject is at least 1 SD (SD: standard deviation) above the average amount of CD8+ effector memory T cells in the refractory group, more preferably at least 2 SD (SD: standard deviation) above the average amount of CD8+ effector memory T cells in the refractory group. When the amount of CD8+ effector memory T cells contained in a blood sample from a pancreatic cancer patient is expressed as a ratio to the amount of T cells (CD8-positive cells) in the peripheral blood, it can be determined that the "amount of CD8-positive effector memory T cells is high" or the "level of CD8-positive effector memory T cells is high" by comparing it with the average ratio of CD8+ effector memory T cells to T cells in a group of pancreatic cancer patients who are refractory to combination therapy with an IL-6 inhibitor and chemotherapy.

[0113] In the present invention, the amount (or level) of CD8+ effector memory T cells contained in a blood sample from a pancreatic cancer patient is preferably expressed as a percentage of the amount of T cells in peripheral blood. As already mentioned, such a percentage can be expressed as a percentage of the number of CD8+ T cells (e.g., CD3+CD8+ cells or CD8+ cells), such as: number of CD3+CD8+ effector memory T cells / number of CD3+CD8+ cells × 100 (%); number of CD8+ effector memory T cells / number of CD8+ cells × 100 (%); or as: CD3+CD8+ effector memory T cell MFI / CD3+CD8+ cell MFI × 100 (%); or CD8+ effector memory T cell MFI / CD8+ cell MFI × 100 (%).

[0114] In a phase I study of TCZ + GN combination therapy described in the Examples of this application, the ratio of CD8+ effector memory T cells to T cells in the peripheral blood of pancreatic cancer patients who were non-responders to combination therapy with an IL-6 inhibitor and chemotherapy was 30% or less, whereas the ratio in the responder group was 30% or more. Currently, it is considered appropriate to compare these values ​​to distinguish between responders and non-responders to TCZ + GN combination therapy. Therefore, in one embodiment of the present invention, a ratio of CD8+ effector memory T cells to T cells of, for example, 30% or more, preferably 40% or more, and particularly preferably 50% or more, is considered to be a "high amount of CD8+ effector memory T cells" or a "high level of CD8+ effector memory T cells."

[0115] The present invention provides a novel use (method of use) of an IL-6 inhibitor in the treatment of pancreatic cancer. Examples of IL-6 inhibitors include, but are not limited to, commercially available preparations containing the anti-IL-6 receptor monoclonal antibodies exemplified above as active ingredients. In one aspect, the present invention provides a therapeutic agent for pancreatic cancer comprising an IL-6 inhibitor, to be administered in combination with a chemotherapeutic agent to pancreatic cancer patients with high levels of blood CD8-positive effector memory T cells. In another aspect, the present invention relates to an IL-6 inhibitor for use in combination with a chemotherapeutic agent to treat pancreatic cancer in pancreatic cancer patients with high levels of blood CD8-positive effector memory T cells. In another aspect, the present invention also relates to the use of an IL-6 inhibitor in the manufacture of a therapeutic agent for pancreatic cancer, in which the IL-6 inhibitor is administered in combination with a chemotherapeutic agent to pancreatic cancer patients with high levels of blood CD8-positive effector memory T cells. In another aspect, the present invention also relates to a method for treating pancreatic cancer, comprising administering an IL-6 inhibitor in combination with a chemotherapeutic agent to pancreatic cancer patients with high levels of blood CD8-positive effector memory T cells.

[0116] In each of the above-mentioned embodiments, "pancreatic cancer patients with high levels of CD8-positive effector memory T cells in the blood" refers to pancreatic cancer patients who have been determined to have a high therapeutic effect from combination therapy of an IL-6 inhibitor and a chemotherapeutic agent. Specifically, "pancreatic cancer patients with high levels of CD8-positive effector memory T cells in the blood" can be patients in whom the ratio of the amount of CD8-positive effector memory T cells to the amount of CD8-positive T cells in the patient's peripheral blood is 30% or more, preferably 40% or more, and particularly preferably 50% or more.

[0117] The present invention will be described in more detail below with reference to the following examples. These examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. An investigator-initiated clinical trial (Phase I) was conducted in 10 patients with unresectable or recurrent pancreatic cancer refractory to gemcitabine hydrochloride (hereinafter referred to as gemcitabine, GEM) and nab-paclitaxel (nab-PTX) therapy. A single dose of the anti-IL-6 receptor antibody tocilizumab (TCZ) was administered in combination with GEM + nab-PTX therapy (Non-Patent Document 5).

[0118] Example 1: Identification of peripheral blood T cell subsets associated with tumor regression effect For the purpose of investigating the clinical significance of peripheral blood T cell subsets before and after TCZ + GN combination therapy in the above-mentioned clinical trial, blood samples were collected three times from patients who received TCZ (IL-6 inhibitor) on the first day, GN (chemotherapy) three times approximately every other week, and the combination of IL-6 inhibitor and chemotherapy on Day 1, Day 9, and Day 28: before administration on the first day (baseline), before GN administration on Day 9 (Day 9), and before GN administration on Day 28 (Day 28).

[0119] To characterize the phenotype of human peripheral blood mononuclear cells (PBMCs), T cell subsets were identified by flow cytometry. Fresh blood was anticoagulated and suspended in 24 volumes of MACS buffer (Miltenyi Biotec) within 2 hours of collection. After centrifugation, the single-cell pellet was suspended in BD Pharm Lyse (BD Biosciences) to lyse red blood cells. PBMCs were then stained for dead cells with Fixable Viability Dye eFluor™ 506 (eBioscience) and subsequently treated with FcR blocking solution (Miltenyi Biotec) to reduce nonspecific binding to target antigens. After staining with antibodies against cell surface antigens at 4°C for 30 minutes, the cells were fixed with Foxp3 / Transcription Factor Staining Buffer Set (eBioscience). After removing the fixative, the cells were stained with antibodies against intracellular antigens for 1 hour at 4°C.

[0120] Table 1 (mentioned above) shows typical examples of markers for identifying single-cell fractions and their combinations for identifying immune cells in peripheral blood. After staining, the cells were centrifuged to remove the supernatant, and then suspended in MACS buffer and analyzed by FACSymphony. TM Each marker was measured by flow cytometry using an A5 measuring instrument (BD Biosciences).

[0121] The measured data were analyzed using FlowJo 10 software (BD Biosciences) by using tools such as circles, ellipses, squares, polygons, and quadrants to enclose (gate) cell populations with common characteristics (e.g., forward scatter (FSC), side scatter (SSC), and marker expression levels) within each single-cell fraction. Specifically, CD45+ leukocytes were selected from PBMCs, and then granulocytes were removed using CD15 and myeloid cells were removed using SSC-A. From these, CD3+ and CD56- T cells were selected. CD4+ T cells were removed from the CD3+ / CD56- / CD4- / CD8+ T cells, and further CD45RA- and CCR7 (CD197)- cells were selected to identify a CD8+ effector memory T cell population with a CD3+ / CD56- / CD8+ / CCR7- / CD45RA- signature.

[0122] For example, if the mean fluorescence intensity (MFI) of CD3 is 4 x 10 3 or higher and CD56 MFI is 2-6 x 10 2 T cells with an MFI of 1 × 10 3 or less and CD8 MFI is 2 × 10 3 These T cells were identified as the CD8+ T cell population. By dividing the CD8+ T cell population into quadrants, subsets of the CD8+ T cell population could be identified. 3 or less and CD45RA MFI is 2 × 10 2 The following CCR7 / CD45RA double-negative CD8+ T cell subpopulation was identified: According to this criterion, a CD8+ effector memory T cell population with CD3+ / CD56- / CD8+ / CCR7- / CD45RA- can be identified.

[0123] As an example, the gating strategy for patient ID GAP01 is shown in Figure 2. CD8+ effector memory T cells were identified by selecting cell populations represented by the CD3+ / CD56- / CD8+ / CCR7- / CD45RA- fraction. The percentages of specific immune cell populations relative to the overall population for patient ID GAP01 are shown in Table 2.

[0124] Example 2: Correlation analysis between specific immune cell populations and combination therapy. Patients were divided into a responder group (4 patients) who showed tumor shrinkage and a non-responder group (6 patients) who did not. We investigated the correlation between immune cell populations in the blood and the effect of combination therapy using IL-6 inhibitor administration and gemcitabine / nab-paclitaxel re-administration. Specifically, we used Welch's t-test to examine the relationship between immune cell subsets, evaluated effect size using Cohen's d, and displayed the results in a volcano plot (Figure 3).

[0125] A volcano plot is a method for visualizing the difference (effect size) and statistical significance (p-value) between each variable in two groups. In this case, Cohen's d, calculated by dividing the difference in the mean values ​​of the variables in the two groups (responder group, non-responder group) by the standard deviation, is plotted on the x-axis, and the p-value, which is an indicator of statistical significance, is converted to a common logarithm and multiplied by -1 and plotted on the y-axis.

[0126] As a result, it was revealed that the percentage of CD8-positive effector memory T cells, expressed as the ratio of the number of CD8-positive effector memory T cells to the total number of CD8-positive T cells, had the highest correlation with Responder.

[0127] Example 3: Baseline blood CD8-positive effector memory T cell levels and antitumor effect In the above-mentioned clinical trial of TCZ + GN combination therapy, the incidence of dose-limiting toxicity was the primary endpoint, but no such events were observed. The response rate was evaluated as a secondary endpoint, with one patient achieving a partial response (PR), seven patients achieving stable disease (SD), and two patients achieving progressive disease (PD). This indicates a favorable antitumor effect in a clinical trial of pancreatic cancer patients who had failed standard treatment (Non-Patent Document 5).

[0128] Blood samples from these 10 cases were subjected to quantification using a flow cytometer, and the number of CD8-positive effector memory T cells, which had the highest correlation with Responder, was used to examine the correlation between the proportion of CD8-positive effector memory T cells, expressed as a percentage of the total CD8-positive T cells, and the anti-tumor effect.

[0129] The results showed that a higher percentage of CD8+ effector memory T cells in the blood before the combination therapy (baseline) correlated with a greater degree of tumor shrinkage (Figure 4, Table 3). This suggests that the percentage of CD8+ effector memory T cells in the blood correlates with the antitumor effect and may be a biomarker for predicting the efficacy of IL-6 inhibitor administration and gemcitabine / nab-paclitaxel combination therapy.

[0130] Example 4: Percentage of CD8-positive effector memory T cells in the blood after the start of treatment and antitumor effect The antitumor effect of combined therapy with IL-6 inhibitor (TCZ) administration and gemcitabine / nab-paclitaxel re-administration was investigated by dividing the patients into a responder group (4 patients) who showed tumor shrinkage and a non-responder group (6 patients) who did not. The number and percentage of CD8-positive effector memory T cells in the blood of these 4 patients were compared with those of 6 patients who did not show tumor shrinkage.

[0131] As a result, the percentage of blood CD8+ effector memory T cells was significantly higher not only before treatment (baseline) but also 9 and 28 days after the start of treatment (Figure 5). No trends were observed for other blood T cell subsets (Figure 6). Therefore, it has become clear that the percentage of blood CD8+ effector memory T cells can be used not only to identify patients who will respond to combination therapy of IL-6 inhibitors and chemotherapy in PDAC patients, but also as a biomarker for predicting the efficacy of combination therapy.

[0132] Example 5: Correlation with symptoms of cachexia The correlation between symptoms of cachexia (weight loss, nausea, and gait disturbance) in patients with advanced pancreatic cancer and the proportion of CD8-positive effector memory T cells in the blood was examined.

[0133] The results showed that a high percentage of CD8+ effector memory T cells in the blood of patients with complete response was associated with a reduced incidence of cachexia symptoms (weight loss, nausea, and gait disturbances) (Figure 7). This correlation was evident not only before but also during combination therapy. These findings suggest that the number or percentage of CD8+ effector memory T cells in the blood may be a useful biomarker for assessing cachexia symptoms in patients receiving IL-6 inhibitor and chemotherapy combination therapy in advanced pancreatic cancer.

[0134] While the foregoing has shown a preferred embodiment of the invention, it will be recognized and understood that various modifications may be made thereto, and the appended claims are intended to cover all such modifications that do not depart from the spirit and scope of the invention.

[0135] Representative embodiments of the present invention are described below. [Embodiment 1] A method for predicting the therapeutic effect of a combination therapy of an IL-6 inhibitor and chemotherapy in a pancreatic cancer patient, comprising the steps of: (i) quantifying the level of CD8-positive effector memory T cells contained in a blood sample collected from the pancreatic cancer patient; and (ii) indicating that the therapeutic effect of the combination therapy is high when the level of CD8-positive effector memory T cells in the patient's blood sample is high.

[0136] [Embodiment 2] The method according to embodiment 1, wherein a higher level of CD8-positive effector memory T cells in the patient's blood sample compared to a predetermined reference level indicates a higher therapeutic effect of the combination therapy.

[0137] [Aspect 3] A method for selecting a pancreatic cancer patient as a target for combination therapy with an IL-6 inhibitor and chemotherapy, the method comprising measuring the level of CD8-positive effector memory T cells in a blood sample from the patient; and when the level of CD8-positive effector memory T cells in the blood sample from the patient is high, the patient is determined to be a target for combination therapy with an IL-6 inhibitor and chemotherapy.

[0138] [Embodiment 4] The method according to embodiment 3, wherein the patient is determined to be a subject to receive combination therapy with an IL-6 inhibitor and chemotherapy when the level of CD8-positive effector memory T cells in the patient's blood sample is higher compared to a predetermined reference level.

[0139] [Aspect 5] The method according to any one of Aspects 1 to 4, wherein the chemotherapy is gemcitabine-based chemotherapy. [Aspect 6] The method according to any one of Aspects 1 to 5, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody.

[0140] [Embodiment 7] The method according to any one of Aspects 1 to 6, wherein the level of CD8-positive effector memory T cells is expressed as a ratio of the number of CD8-positive effector memory T cells, or a measured value that is an indicator of the number of CD8-positive T cells, to the number of CD8-positive T cells in a blood sample of the patient, or a measured value that is an indicator of the number of CD8-positive T cells.

[0141] [Aspect 8] The method of Aspect 7, wherein the proportion of 30% or more indicates a high level of CD8-positive effector memory T cells in the patient's blood sample.

[0142] [Aspect 9] A therapeutic agent comprising a combination of an IL-6 inhibitor and a chemotherapeutic agent, to be administered to a pancreatic cancer patient who has been determined to be highly likely to benefit from combined therapy with an IL-6 inhibitor and chemotherapy, using the level of blood CD8-positive effector memory T cells as an indicator.

[0143] [Embodiment 10] An IL-6 inhibitor for administration in combination with a chemotherapeutic agent to a pancreatic cancer patient who has been determined to be likely to benefit from a combination therapy of an IL-6 inhibitor and chemotherapy, based on the level of blood CD8-positive effector memory T cells as an indicator.

[0144] [Aspect 11] The therapeutic agent of Aspect 9 or the IL-6 inhibitor of Aspect 10, wherein the therapeutic effect of the combination therapy is determined to be high when the level of the number of CD8-positive effector memory T cells in a blood sample of a patient is high compared to a predetermined reference level.

[0145] [Embodiment 12] The therapeutic agent of embodiment 9 or the IL-6 inhibitor of embodiment 10, wherein the level of CD8-positive effector memory T cells is expressed as a ratio of the number of CD8-positive effector memory T cells, or a measured value that is an indicator of the number of CD8-positive T cells, to the number of CD8-positive T cells in a blood sample from the patient, or a measured value that is an indicator of the number of CD8-positive T cells.

[0146] [Aspect 13] The therapeutic agent or IL-6 inhibitor according to Aspect 12, wherein the therapeutic effect of the combination therapy of an IL-6 inhibitor and chemotherapy is determined to be high when the ratio is 30% or more.

[0147] [Embodiment 14] The therapeutic agent or IL-6 inhibitor according to any one of embodiments 9 to 13, wherein the chemotherapy is gemcitabine-based chemotherapy.

[0148] [Aspect 15] The therapeutic agent or IL-6 inhibitor according to any one of Aspects 9 to 13, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody.

[0149] [Aspect 16] The therapeutic agent or IL-6 inhibitor according to any one of Aspects 9 to 13, wherein the high therapeutic effect includes an improvement in tumor shrinkage rate or an alleviation of cachexia symptoms.

[0150] [Embodiment 17] A kit for predicting the efficacy of a combination therapy of an IL-6 inhibitor and chemotherapy or for selecting patients who are expected to benefit most from the combination therapy, the kit comprising an antibody capable of identifying CD8-positive effector memory T cells.

[0151] [Embodiment 18] The kit according to embodiment 17, wherein the antibody capable of identifying CD8-positive effector memory T cells is used to measure the amount of CD8-positive effector memory T cells contained in a blood sample from a pancreatic cancer patient.

[0152] [Embodiment 19] The kit according to Aspect 17 or 18, wherein the antibodies capable of identifying CD8-positive effector memory T cells comprise five or more types of antibodies, including an anti-CD3 antibody, a CD56 antibody, an anti-CD8 antibody, an anti-CCR7 antibody, and an anti-CD45RA antibody or an anti-CD45RO antibody.

[0153] [Aspect 20] A pharmaceutical comprising an anti-IL-6 receptor antibody intended for administration to pancreatic cancer patients determined to be susceptible to a high therapeutic effect of combined therapy with an anti-IL-6 receptor antibody and chemotherapy, wherein the patient is determined to be susceptible to a high therapeutic effect if the ratio of the amount of CD8-positive effector memory T cells to the amount of CD8-positive T cells in the peripheral blood is 30% or more, and the pharmaceutical comprising an anti-IL-6 receptor antibody is to be administered to said patient in combination with a chemotherapeutic agent.

Claims

1. A method for predicting the therapeutic effect of a combination therapy of an IL-6 inhibitor and chemotherapy in a pancreatic cancer patient, the method comprising the steps of: (i) quantifying the level of CD8-positive effector memory T cells contained in a blood sample collected from the pancreatic cancer patient; and (ii) indicating that the therapeutic effect of the combination therapy is high when the level of CD8-positive effector memory T cells in the patient's blood sample is high.

2. The method of claim 1, wherein a higher level of CD8-positive effector memory T cells in the patient's blood sample compared to a predetermined reference level indicates a higher therapeutic effect of the combination therapy.

3. A method for selecting a pancreatic cancer patient for combination therapy with an IL-6 inhibitor and chemotherapy, the method comprising measuring the level of CD8-positive effector memory T cells in a blood sample from the patient; and when the level of CD8-positive effector memory T cells in the blood sample from the patient is high, the patient is determined to be a candidate for combination therapy with an IL-6 inhibitor and chemotherapy.

4. The method according to claim 3, wherein a patient is determined to be a candidate for combination therapy with an IL-6 inhibitor and chemotherapy if the patient has a higher level of CD8-positive effector memory T cells in a blood sample compared to a predetermined reference level.

5. The method according to any one of claims 1 to 4, wherein the chemotherapy is gemcitabine-based chemotherapy.

6. The method according to any one of claims 1 to 4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody.

7. The method according to any one of claims 1 to 4, wherein the level of CD8-positive effector memory T cells is expressed as the ratio of the number of CD8-positive effector memory T cells or a measured value indicative of the number of CD8-positive T cells or a measured value indicative of the number of CD8-positive T cells in a blood sample of the patient.

8. The method of claim 7, wherein a ratio of 30% or greater indicates a high level of CD8-positive effector memory T cells in the patient's blood sample.

9. A therapeutic agent comprising a combination of an IL-6 inhibitor and a chemotherapeutic agent, for administration to a pancreatic cancer patient who has been determined to have a high therapeutic effect from combined therapy with an IL-6 inhibitor and chemotherapy, using the level of blood CD8-positive effector memory T cells as an indicator.

10. An IL-6 inhibitor to be administered in combination with a chemotherapy agent to a pancreatic cancer patient who has been determined to have a high therapeutic effect from combination therapy of an IL-6 inhibitor and chemotherapy, based on the level of blood CD8-positive effector memory T cells as an indicator.

11. The therapeutic agent of claim 9 or the IL-6 inhibitor of claim 10, wherein the therapeutic effect of the combination therapy is determined to be high when the level of CD8-positive effector memory T cells in a patient's blood sample is high compared to a predetermined reference level.

12. The therapeutic agent of claim 9 or the IL-6 inhibitor of claim 10, wherein the level of CD8-positive effector memory T cells is expressed as the ratio of the number of CD8-positive effector memory T cells or a measured value that is an indicator of the number of CD8-positive T cells or a measured value that is an indicator of the number of CD8-positive T cells in a blood sample of the patient or a measured value that is an indicator of the number of CD8-positive T cells.

13. The therapeutic agent or IL-6 inhibitor according to claim 12, wherein the therapeutic effect of the combination therapy of an IL-6 inhibitor and chemotherapy is determined to be high when the ratio is 30% or more.

14. The therapeutic agent of claim 9 or the IL-6 inhibitor of claim 10, wherein the chemotherapy is gemcitabine-based chemotherapy.

15. The therapeutic agent of claim 9 or the IL-6 inhibitor of claim 10, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody.

16. The therapeutic agent of claim 9 or the IL-6 inhibitor of claim 10, wherein the high therapeutic effect includes an improvement in the tumor shrinkage rate or an alleviation of the symptoms of cachexia.

17. A kit for predicting the efficacy of a combination therapy of an IL-6 inhibitor and chemotherapy, or for selecting patients who are expected to benefit most from said combination therapy, comprising an antibody capable of identifying CD8-positive effector memory T cells.

18. The kit described in claim 17, wherein the antibody capable of identifying CD8-positive effector memory T cells is used to measure the amount of CD8-positive effector memory T cells contained in a blood sample from a pancreatic cancer patient.

19. The kit described in claim 17 or 18, wherein the antibodies capable of distinguishing CD8-positive effector memory T cells comprise five or more types of antibodies including an anti-CD3 antibody, a CD56 antibody, an anti-CD8 antibody, an anti-CCR7 antibody, and an anti-CD45RA antibody or an anti-CD45RO antibody.

20. A pharmaceutical containing an anti-IL-6 receptor antibody intended for administration to pancreatic cancer patients determined to have a high therapeutic effect from combined therapy with an anti-IL-6 receptor antibody and chemotherapy, wherein the patient is determined to have a high therapeutic effect if the ratio of CD8-positive effector memory T cells to the amount of CD8-positive T cells in the peripheral blood is 30% or more, and the pharmaceutical containing an anti-IL-6 receptor antibody is to be administered to said patient in combination with a chemotherapeutic agent.

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