Application of neutrophil number in prediction of tumor treatment effect of oncolytic virus

Abstract

The invention discloses an application of the number of neutrophils in predicting the curative effect of oncolytic viruses in treating tumors. In the application, the neutrophile granulocyte number level in the blood of a tumor patient is closely associated with the tumor treatment effect, and the applicable tumor syndromes are common, including melanoma, colorectal cancer, esophageal cancer, head and neck tumors, gastric cancer, biliary tract system tumors, sarcoma and other tumors. In the application, the critical value of the number of neutrophils for predicting the tumor treatment effect is 2 * 10 < 9 >-5.5 * 10 < 9 > / L, and the most preferable critical value is 4.0 * 10 < 9 > / L; the curative effect of OH2 single-drug treatment on tumor patients with the neutrophil number level below a critical value is better than that of tumor patients with the neutrophil number level above the critical value.

Description

Technical Field

[0001] The present application relates to the technical field of tumor efficacy prediction, and specifically to the application of neutrophil count in predicting the efficacy of oncolytic virus therapy for tumors. Background Art

[0002] Cancer is a major disease that affects and endangers people's physical health and life safety, and has long ranked among the top two causes of disease mortality. Cancer is also a large group of diseases that can arise from almost any organ or tissue in the body. Abnormal cells grow uncontrollably, dividing and growing without limit, exceeding their usual boundaries, invading adjacent parts of the body and / or spreading to other organs. Tumors and malignant tumors are other common names for cancer. There are many types of tumors, which can be divided into brain tumors, liver tumors, digestive tract tumors, melanoma, etc. according to the location of the disease. There are many ways to treat tumors, the most common of which are surgery, radiotherapy, chemotherapy, molecular targeted therapy, and immunotherapy.

[0003] Oncolytic virus (OV) therapy is a new anti-tumor approach that uses viruses to attack cells to destroy tumor tissue. Oncolytic viruses are viruses that can infect and destroy tumor cells. They can selectively target and dissolve tumor cells while sparing normal cells. The anti-tumor effect of OV depends on the induction of local and systemic immune responses. OVs preferentially replicate in malignant cells and ultimately induce tumor cell death. In addition, virus-mediated lysis releases tumor-associated antigens, which very effectively stimulate the immune system and promote the induction of anti-tumor immunity. Although some viruses are naturally oncolytic, most OVs are genetically engineered to increase tumor selectivity and improve efficacy. More than 40 OVs from at least 10 different virus families have entered clinical development. In a phase Ib trial for the treatment of advanced melanoma, OV combined with immune checkpoint inhibitors (ICIs) significantly increased CD8 + T cell infiltration rate and response rate. However, an international randomized, double-blind, multicenter phase III trial study from J Clin Oncol showed that adding T-VEC (a recombinant herpes simplex virus-1 approved for use by the FDA and other regulatory agencies) to programmed death receptor 1 (PD-1) inhibitors did not significantly improve patient survival outcomes compared with placebo.

[0004] OH2 is a recombinant herpes simplex virus type 2 (HSV-2) that selectively replicates in tumor cells. The OH2 virus has been depleted of the ICP34.5 and ICP47 genes of wild-type HSV-2, reducing virulence and enhancing oncolytic activity. In addition to these deletions, a human GM-CSF gene expression cassette has been inserted into the OH2 virus, mediating GM-CSF protein expression in the tumor microenvironment and thereby enhancing the host immune response. The OH2 virus differs from T-VEC in that its backbone is derived from HSV-2. Preclinical studies have demonstrated that HSV-2 (similar to OH2) exhibits superior tumor suppression compared to HSV-1 (similar to T-VEC) in several tumor-bearing animal models, including breast, colon, and metastatic ovarian cancer. Consequently, OH2 has made clinical progress and is currently undergoing late-stage clinical trials. A Phase Ia / Ib clinical trial has been conducted in China for patients with unresectable Stage III-IV melanoma, most of whom have acral melanoma, to evaluate the safety and preliminary efficacy of OH2. OH2 oncolytic virus therapy has demonstrated a favorable safety profile with no dose-limiting toxicities and has demonstrated durable anti-tumor efficacy in melanoma patients, particularly those who have progressed after PD-1 therapy.

[0005] With the gradual deepening of clinical research, the application of OH2 oncolytic virus in tumor treatment is becoming more and more extensive. Its treatment is mainly aimed at patients with solid tumors, including melanoma, colorectal cancer, glioma, esophageal cancer, head and neck tumors, gastric cancer, biliary system tumors, sarcoma, etc. Tumor immunotherapy is affected by many factors, which also leads to the fact that the efficacy of OH2 oncolytic virus in different patients still varies. Therefore, OH2 treatment of tumors requires efficient and convenient predictive factors to timely and accurately identify responding populations, optimize treatment plans, improve treatment effects, and avoid or reduce unnecessary economic burdens on non-responding populations. Summary of the Invention

[0006] In view of this, the purpose of this application is to provide an application of neutrophil count in predicting the efficacy of oncolytic virus treatment of tumors. In this application, by testing the neutrophil count level of tumor patients, it is not only helpful to more accurately screen the tumor patient group suitable for OH2 treatment, but also to provide a scientific basis for optimizing the OH2 treatment plan and improving the OH2 treatment effect.

[0007] To achieve or at least partially achieve the above objectives, this application provides at least the following technical solutions:

[0008] The application of neutrophil count in predicting the efficacy of oncolytic virus treatment of tumors, wherein the neutrophil count level is the neutrophil count level in the blood of tumor patients before tumor treatment.

[0009] Compared with the existing technology, the technical solution provided by this application has at least the following beneficial effects:

[0010] 1. As verified by the examples of this application, the neutrophil count level of tumor patients before treatment is closely correlated with the efficacy of tumor treatment. Therefore, the neutrophil count level can be used as an efficacy predictor to more accurately screen patient groups suitable for OH2 treatment, providing a scientific basis for optimizing treatment plans and improving treatment effects.

[0011] 2. The technical solution provided in this application has a simple detection method, low cost, and good stability, and can become a potential predictive tool for clinicians. DETAILED DESCRIPTION

[0012] In order to make the purpose, technical solutions and advantages of this application more clear, the following further describes this application in detail with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit this application.

[0013] In the text of this application, the term "T-VEC (Talimogene Laherparepvec)", also known as "Imlygic", is a genetically modified herpes simplex virus type 1 (HSV-1). It is the first oncolytic virus drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of melanoma patients with skin, subcutaneous and lymph node lesions after initial surgery. T-VEC is injected intratumorally and can selectively replicate in tumor cells, causing tumor cells to rupture and die, while locally releasing GM-CSF (granulocyte-macrophage colony-stimulating factor) in the tumor tissue, which is a white blood cell growth factor that can activate systemic immune responses. The mechanism of action of T-VEC includes inducing tumor tissue dissolution and stimulating a systemic anti-tumor immune response. As an oncolytic virus drug, T-VEC still needs further improvement in the treatment of patients with advanced melanoma or PD-1 resistant melanoma.

[0014] As used herein, the term "OH2" or "OH2 virus" refers to a recombinant oncolytic herpes simplex virus type 2. The virus was constructed by deleting the neurotoxic gene ICP34.5 and the immunosuppressive gene ICP47 from the viral genome using molecular cloning and DNA (not evaluated) homologous recombination techniques, and inserting a human hGM-CSF expression cassette into the ICP34.5 region. The nucleotide sequence of the expression cassette is shown in SEQ ID NO: 1. The "OH2 virus" strain is designated H2d3d4-hGF and is designated as herpes simplex virus type 2 (Latin name: Herpes Simplex Virus Type 2). The depository is the General Microbiology Center of the China Culture Collection Administration, located at the Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing. The deposit number is CGMCC No. 3600, and the date of deposit is February 3, 2010. In the text of this application, "OH2" or "OH2 virus" as an oncolytic virus that can kill tumor cells should be interpreted as an anti-tumor drug in the specific context of this application.

[0015] In this application, the term "injection" refers to sterile solutions (including emulsions and suspensions) of pharmaceuticals for injection into the body, as well as sterile powders or concentrated solutions for preparation into solutions or suspensions prior to use. Injections act rapidly and reliably, are unaffected by pH, enzymes, food, and other factors, exhibit no first-pass effect, and can exert systemic or localized effects. They are suitable for patients who are not suitable for oral medication or cannot take oral medication. It should be understood that, as used in this application, "OH2 injection" consists of "OH2 virus" particles and a buffer that preserves the "OH2 virus."

[0016] In the text of this application, the term "OH2 treatment" should be understood as treatment with "OH2 virus" or "OH2 virus preparation", such as treatment with "OH2 injection".

[0017] In the text of this application, the term "RECIST" refers to the criteria for evaluating the efficacy of immunotherapy for solid tumors, which is a set of standards for evaluating the efficacy of anti-tumor treatment. It was first developed by the National Cancer Institute of the United States and the National Cancer Institute of Canada in 2000 (v1.0) and revised and republished in 2009 (v1.1). The RECIST standard provides a definition of tumor treatment efficacy, including complete remission (CR), partial remission (PR), stable disease (SD) and progressive disease (PD). The term "iRECIST" is a guideline for evaluating the efficacy of immunotherapy based on the revised RECIST 1.1 standard, specifically for immunotherapy clinical trials for solid tumors. "iRECIST" addresses the limitations of "RECIST 1.1" in immunotherapy by introducing the concepts of "unconfirmed progression" and "confirmed progression", improves the accuracy of evaluating the efficacy of immunotherapy, prolongs the assessment of progression-free survival, and better reflects the patient's survival benefit.

[0018] In this application, the term "OS" stands for Overall Survival. In medical research, particularly in oncology, OS is an important efficacy evaluation metric, measuring the time from randomization (or start of treatment) to patient death. OS is the gold standard for evaluating the long-term effects of anti-cancer therapy because it directly reflects the impact of treatment on patient survival.

[0019] In this application, the term "PFS" is the abbreviation of Progression-Free Survival, which refers to the time from the start of randomization (or the start of treatment in a single-arm trial) to tumor progression or death from any cause (whichever occurs first). This indicator is very important in cancer clinical trials because it provides an intermediate endpoint for measuring treatment efficacy and can evaluate treatment efficacy earlier than overall survival (OS).

[0020] In the text of this application, the term "iORR" is an indicator related to the evaluation of the therapeutic efficacy of tumors (solid tumors only), and "objective response rate (iORR)" refers to the sum of the proportions of partial response (iPR) and complete response (iCR) of immune efficacy; the higher the iORR, the more patients achieved tumor shrinkage using this immunotherapy method.

[0021] In this application, the term "DCR" is the abbreviation of Disease Control Rate, which is an indicator used to evaluate the effectiveness of tumor treatment. It describes the percentage of patients with advanced cancer who achieve complete remission (CR), partial remission (PR), or stable disease (SD) after treatment intervention. Specifically, the DCR calculation formula is: DCR = (CR + PR + SD) / evaluable number of cases, that is, the percentage of cases that achieve remission (including complete remission and partial remission) and stable disease after treatment to the number of evaluable cases.

[0022] In this application text, the term "mOS" stands for median overall survival, also known as half survival. It refers to the survival time corresponding to a cumulative survival rate of 0.5, that is, 50% of patients can survive this period of time. Median survival is an indicator for evaluating the efficacy of cancer patients' survival. Generally speaking, median survival refers to the time when 50% of patients can still survive after a certain treatment. Median survival is often used to judge the prognosis of patients with malignant tumors. The longer the median survival time, the longer the overall survival time of malignant tumor patients. In addition, the length of median survival can also judge the effectiveness of new treatment options. If clinical studies find that the median survival time of patients after receiving a certain treatment option is prolonged, or significantly exceeds the survival time of the current standard treatment option, then the new treatment option can usually be recommended or applied in clinical treatment, bringing certain benefits to patients, such as increasing the patient's survival rate and improving the patient's quality of life.

[0023] In this application, the term "ANC" is the abbreviation of Absolute Neutrophil Count, which refers to the number of neutrophils in the blood. The term "baseline ANC" refers to the number of neutrophils in the blood of a patient or subject before receiving a cancer treatment regimen.

[0024] In this application, the term "cutoff value" refers to a predetermined boundary value (critical value) or threshold used to distinguish different results (e.g., normal from abnormal, negative from positive). A "cutoff value" is derived based on statistical principles and large-sample data analysis to determine whether a medical indicator exceeds the normal range and, therefore, whether intervention or treatment is necessary.

[0025] In the text of this application, the term "preferably" is only used to describe an implementation method or example with better effects. It should be understood that it does not constitute a limitation on the scope of protection of the present invention.

[0026] Neutrophils are an important type of white blood cells, and they play a vital role in the human immune system. The normal count level of neutrophils is very important for assessing the health status of an individual. However, the existing technology still lacks research on the correlation between the level of neutrophil count and the efficacy of tumor treatment, and there is no research on the correlation between the level of neutrophil count and the efficacy of tumor treatment, let alone the use of neutrophil count as a predictor for predicting the efficacy of treatment or guiding oncolytic virus therapy in the field of oncolytic virus treatment of tumors. In the embodiment of this application, regardless of cancer indications, a comprehensive analysis of biomarker-related data and efficacy evaluation indicators was conducted in the Phase I / II study of OH2 virus for tumor treatment, aiming to verify the role of ANC as a prognostic factor for melanoma and other cancers, examine its relationship with the clinical response of OH2 virus treatment of tumors, and identify a new biomarker, namely ANC, in melanoma and other cancers treated with OH2. The results of the study revealed the previously unappreciated biological effects of OH2 in tumor treatment and provided support for personalized cancer prognosis.

[0027] Based on this, the embodiments of the present application provide the application of neutrophil count in predicting the efficacy of oncolytic virus treatment of tumors, wherein the neutrophil count level is the neutrophil count level in the blood of tumor patients before tumor treatment.

[0028] In certain embodiments, in the application, the oncolytic virus therapy is OH2 oncolytic virus monotherapy.

[0029] In certain embodiments, in the application, the neutrophil count is used to predict the efficacy of tumor treatment, and the critical value of the neutrophil count for predicting the efficacy of tumor treatment is 2×10 9 ~5.5×10 9 / L; when the tumor patients have a baseline ANC level below the critical value before receiving treatment, the efficacy of OH2 monotherapy in the tumor subjects is better than that in the tumor subjects with a baseline ANC level above the critical value.

[0030] In certain preferred embodiments, in the application, the neutrophil count is used to predict the efficacy of tumor treatment, and the critical value of the neutrophil count for predicting the efficacy of tumor treatment is 3.8×10 9 ~4.1×10 9 / L; when the tumor patients have a baseline ANC level below the critical value before receiving treatment, the efficacy of OH2 monotherapy in the tumor subjects is better than that in the tumor subjects with a baseline ANC level above the critical value.

[0031] In certain more preferred embodiments, in the application, the neutrophil count is used to predict the efficacy of tumor treatment, and the critical value of the neutrophil count for predicting the efficacy of tumor treatment is 4.0×10 9 / L; before cancer patients receive treatment, the baseline ANC level in the blood is 4.0×10 9 The efficacy of OH2 monotherapy in patients with tumors below 4.0×10 / L was better than that in patients with baseline ANC levels above 4.0×10 9 / L tumor subjects receiving OH2 monotherapy.

[0032] In certain embodiments, in the application, the applicable tumor types include at least one of melanoma, colorectal cancer, esophageal cancer, head and neck tumors, gastric cancer, biliary system tumors, and sarcoma.

[0033] In certain embodiments, in the application, the sample used to detect the level of neutrophil count is peripheral blood of a tumor patient.

[0034] The examples of the present application provide a clinical application trial of neutrophil count levels in predicting the efficacy of OH2 monotherapy for tumors. This clinical trial prospectively analyzed patients receiving OH2 monotherapy. The clinical trial was approved by an independent committee of the clinical institution, and all subjects participating in the treatment signed an informed consent form before enrollment.

[0035] Two immunotherapy cohorts were established throughout the clinical trial: the first cohort (N = 44 subjects, melanoma) receiving OH2 monotherapy; and the second cohort (N = 71 subjects, other cancers except melanoma) receiving OH2 monotherapy. Biomarkers and cutoff values for predicting OH2 treatment efficacy were identified from the clinical data of the first cohort. In the second step, these biomarkers and cutoff values were further validated using clinical data. Details of the clinical trial are provided below.

[0036] Clinical trial materials and methods

[0037] 1. Subject inclusion criteria

[0038] 1.1 Inclusion Criteria

[0039] (1) Aged 18 to 75 years (including the cutoff value), male or female; (2) Patients with a clear diagnosis of malignant tumors by pathology or cytology, such as digestive system tumors, head and neck tumors, soft tissue sarcomas, melanoma, etc.; (3) Patients with advanced (unresectable or recurrent / metastatic) disease who have failed standard treatment (disease progression or intolerance) or lack effective treatment methods; (4) Patients with ECOG general status score 0-1 points; (5) Expected survival time is more than 3 months; (6) Previous anti-tumor treatment (including endocrine, chemo / radiotherapy, targeted therapy) has been completed for more than 4 weeks (patients using nitrosourea and mitomycin chemotherapy should stop the drug for more than 6 weeks), and the adverse reactions of the previous treatment have recovered to level 1; (7) Patients who have undergone major surgery must wait for 4 weeks after surgery; (8) At least one measurable or evaluable lesion; (9) There is a lesion suitable for intratumoral injection (the long diameter of the lesion is at least greater than or equal to 0.5 cm); (10) Patients with asymptomatic central nervous system metastasis or asymptomatic brain metastasis after treatment must have no disease progression by computed tomography (CT) or magnetic resonance imaging (MRI), be stable for at least 3 months, and do not require steroid treatment for at least 4 weeks; (11) Laboratory examination: WBC ≥ 3.0×10 9 / L, ANC≥1.5×10 9 / L,PLT≥100×10 9 / L, Hb ≥ 90g / L; blood BUN and blood creatinine are within 1.5 times the upper limit of normal; TBIL ≤ 1.5 times the upper limit of normal; ALT and AST ≤ 2.5 times the upper limit of normal; patients with liver metastasis do not exceed 5 times the upper limit of normal; coagulation function is normal (PT, APTT are within 1.5 times the upper limit of normal); (12) female subjects and their spouses receive effective contraception during treatment and within 3 months after treatment; (13) subjects with herpes need to wait for 3 months after the end of herpes; (14) voluntarily sign the informed consent form, and good compliance is expected.

[0040] 1.2 Exclusion criteria:

[0041] (1) Subjects with serious medical diseases, including serious heart disease, cerebrovascular disease, uncontrolled diabetes, uncontrolled hypertension, severe infection, active gastrointestinal ulcer; (2) Subjects with clinical symptoms of brain metastasis; (3) Subjects with active infection or unexplained fever > 38.5℃ during the screening period and before the first dose; (4) Subjects with congenital or acquired immune deficiency (such as HIV infection) or active hepatitis (Hepatitis B reference: HbsAg, Anti-HBs, HBeAg, Anti-HBc, Anti-HBe, HBV DNA (not evaluated) ≥104 / mL, hepatocyte transaminase, etc.; hepatitis C reference: HCV antibodies and HCV RNA (not evaluated), etc.); (5) lesions cannot meet the requirement of 1mL injection volume in the tumor; (6) pregnant or lactating women; (7) other experimental drugs or antiviral treatments have been used or are being used within 4 weeks before treatment; (8) have participated in other clinical studies within the past 4 weeks; (9) patients who are allergic to herpes virus and drug ingredients; (10) subjects are known to have a history of psychotropic drug abuse, alcoholism or drug abuse; (11) patients with other malignant tumors within 5 years before enrollment, excluding effectively resected cervical carcinoma in situ, low-risk gastrointestinal stromal exclusion standard tumors, breast cancer, skin basal cell carcinoma, skin squamous cell carcinoma, and papillary thyroid carcinoma; (12) patients with active autoimmune diseases or a history of autoimmune diseases but with the possibility of recurrence, but patients with the following diseases are not excluded and can be further screened: a. type I diabetes, b. hypothyroidism (if only (13) Patients with any condition requiring systemic treatment with corticosteroids (prednisone > 10 mg / day or equivalent dose of similar drugs) or other immunosuppressants within 14 days prior to study drug administration, but patients who are currently or have previously used any of the following steroid regimens can be included: a. Epinephrine-replacing steroids (prednisone ≤ 10 mg / day or equivalent dose of similar drugs), b. Topical, ophthalmic, intra-articular, intranasal or inhaled corticosteroids with minimal systemic absorption, c. Short-term (≤ 7 days) use of corticosteroids for prophylaxis (e.g., allergy to contrast agents) or for treatment of non-autoimmune diseases (e.g., delayed hypersensitivity reactions caused by contact allergens); (14) Patients who are deemed by the investigator to be unsuitable for participation in this trial for any reason.

[0042] 2. Treatment and assessment methods

[0043] 2.1 Treatment Modality: OH2 is delivered via intratumoral injection, either directly into the skin or subcutaneous lesions or under ultrasound guidance for deep lymph node or organ metastases. The volume injected into each lesion is based on the longest diameter of the tumor: ≤1.5 cm, maximum 1 mL; >1.5 to ≤2.5 cm, maximum 2 mL; >2.5 to ≤5.0 cm, maximum 4 mL; >5 cm, maximum 8 mL. Multiple tumor tissues are permitted. There is no limit to the number of lesions that can be injected per patient, but the maximum volume that can be injected during each visit is 8 mL.

[0044] 2.2 Efficacy evaluation: The clinical efficacy of solid tumors was evaluated according to the iRECIST criteria.

[0045] 3. Statistical Analysis Methods

[0046] Descriptive statistics were used to describe the baseline characteristics of the patients. 2- The association between ANC and patient characteristics was analyzed using the sham-test and Mann-Whitney U tests. A comprehensive survival analysis was performed for overall survival (OS) and progression-free survival (PFS). Survival analysis was performed using the Kaplan-Meier method and the log-rank test. A univariate Cox proportional hazards regression model was further applied to identify independent prognostic factors for ANC, adjusting for potential confounding variables such as age, sex, Eastern Cooperative Oncology Group (ECOG) score, number of previous treatment lines, clinical stage, and duration of OH2 treatment. Results were presented as hazard ratios (HRs) and 95% confidence intervals (95% CIs).

[0047] 4. Results and Analysis

[0048] The present application examples further analyze the relationship between the therapeutic efficacy of each test group and the absolute neutrophil count (ANC), where the ANC value is the baseline ANC, that is, the neutrophil count in the blood of each subject before receiving the treatment regimen.

[0049] Table 1 shows the correlation results between different baseline ANC levels and the best overall efficacy (BOR) in the first test group of patients (melanoma indication Ia / Ib, n=44) after receiving OH2 monotherapy.

[0050] Table 1

[0051] BOR <![CDATA[ANC average value (10 9 / L)]]> PR (n=10) 3.1 SD (n=14) 3.6 PD (n=18) 4.0 Not assessed*(n=2) 5.4

[0052] As can be seen from Table 1, the best overall therapeutic effect of the 10 subjects was PR, and the average ANC value was 3.1×10 9 / L, the best overall therapeutic effect of 14 subjects was SD, and the average ANC value was 3.6×10 9 / L, the best overall therapeutic effect of 18 subjects was PD, and the average ANC value was 4.0×10 9 / L, these results indicate that the ANC level of melanoma patients is inversely correlated with the clinical efficacy of OH2 monotherapy, that is, subjects with low ANC values can benefit more from OH2 monotherapy than subjects with high ANC values.

[0053] To define the high ANC population, the third quartile of ANC values among the 44 subjects in the first test group was selected as the absolute cutoff value (4.44 × 10 9 / L) and was used for further univariate group analysis. Table 2 shows the univariate group analysis results of iPFS and iORR factors in the first test group (OH2 monotherapy), including iPFS (HR=0.3; 95%CI 0.1-0.7; P=0.007), iORR (OR=8.5; 95%CI 0.5-159.8; P=0.100). The results showed that the low ANC population (ANC≤4.4) had a better prognosis and a higher response rate. OH2 monotherapy in the low ANC population significantly enriched patients with better sustained partial remission (PR) and stable disease (SD), and both the objective response rate (iORR) and disease control rate (DCR) were significantly improved.

[0054] Table 2

[0055]

[0056] In order to determine the optimal cutoff point of baseline ANC, the present embodiment used different baseline ANC cutoff values (2.0×10 9 / L, 2.5×10 9 / L, 3.0×10 9 / L, 3.5×10 9 / L, 4.0×10 9 / L, 4.5×10 9 / L, 5.0×10 9 / L, 5.5×10 9 The results of univariate group analysis are shown in Table 3.

[0057] Table 3

[0058]

[0059]

[0060] From the results in Table 3, we can see that the baseline ANC critical values are 2.0×10 9 / L, 2.5×10 9 / L, 3.0×109 / L, 3.5×10 9 / L, 4.0×10 9 / L, 4.5×10 9 / L, 5.0×10 9 / L, 5.5×10 9 / L, the efficacy of OH2 monotherapy in cancer patients whose baseline ANC levels were below the critical values was significantly better than that in cancer patients whose baseline ANC levels were above the critical values. This indicates that the critical value of baseline ANC can be selected from 2.0×10 9 ~5.5×10 9 From the results in Table 3, it can be seen that only at 4.0×10 9 When the cutoff value of 4.0×10 / L was used, the difference in PFS and iORR was statistically significant. 9 / L can be used as the optimal cutoff value for baseline ANC level.

[0061] In order to explore the optimal critical value range of baseline ANC level, a 3.6×10 9 / L, 3.7×10 9 / L, 3.8×10 9 / L, 3.9×10 9 / L, 4.1×10 9 / L, 4.2×10 9 / L, 4.3×10 9 / L, 4.4×10 9 The optimal cutoff values of 8 baseline ANC levels, including 1 / 2L, were used for univariate group analysis. The analysis results are shown in Table 4.

[0062] Table 4

[0063]

[0064] From the results in Table 4, we can see that the baseline ANC is only 3.8×10 9 / L, 3.9×10 9 / L, 4.0×10 9 / L, 4.1×10 9 When the cutoff value of 3.8×10 / L was used, the difference in miPFS and iORR was statistically significant. 9 ~4.1×10 9 Any value in 1 / 2L is used as the preferred baseline ANC cutoff value.

[0065] Take 4.0×10 9 / L is the ANC cutoff value, and the 44 subjects in the first test group were divided into the high ANC group (ANC>4.0×10 9 / L) and low ANC group (ANC≤4.0×10 9 / L), and the miPFS, iORR, and DCR of this group of subjects were analyzed. The results are shown in Table 5.

[0066] Table 5

[0067]

[0068] From the results in Table 5, we can see that the low ANC group (ANC≤4.0×10 9 / L) of the cohort, the iORR (objective response rate) was 34.5%, the DCR (disease control rate) was 69%, and the miPFS (median progression-free survival) was 3.7 months; in contrast, in the high ANC group (ANC>4.0×10 9 In the cohort of subjects with a baseline ANC of 4.0×10-4, the iORR (objective response rate) was 0, the DCR (disease control rate) was 38.5%, and the miPFS (median progression-free survival) was 1.8 months. miPFS (HR = 2.9; 95% CI 1.4-6.1), iORR (OR = 0.1; 95% CI 0.0-1.3), and DCR (OR = 0.3; 95% CI 0.1-1.1) showed that the prognosis of the high ANC population (ANC>4) was worse and the response rate was lower. The above results show that the cutoff value of baseline ANC is set at 4.0×10-4. 9 / L can accurately predict the best efficacy of OH2 monotherapy in melanoma patients, that is, baseline ANC>4.0×10 9 / L, the response rate of patients receiving OH2 monotherapy was low, and the baseline ANC was ≤4.0×10 9 When the ANC was ≤4.0×10 / L, the patients had a higher response rate to OH2 monotherapy. 9 Melanoma patients with HBV / L are more likely to benefit from OH2 monotherapy.

[0069] From November 2018 to March 2023, 44 melanoma patients in the first cohort were enrolled in the clinical trial (NCT04386967) and received OH2 monotherapy, of whom 15 had a baseline ANC > 4.0 × 10 9 / L, and the baseline ANC of the other 29 patients was ≤4.0×10 9 / L, detailed patient demographic characteristics are shown in Table 6.

[0070] In addition, 71 patients with non-melanoma solid tumors (the second trial group) who received OH2 monotherapy from a multi-cohort, multi-indication Class I / II clinical trial (NCT03866525) were also included in the analysis. Most patients (n = 30) had colorectal cancer, and 30 of them had a baseline ANC > 4.0 × 10 9 / L, and the baseline ANC of another 41 patients was ≤4.0×10 9 / L. Detailed patient demographic characteristics are shown in Table 6. The data showed that baseline factors such as age, gender, disease, and disease stage did not reach statistical significance (all P>0.05), and no significant differences were observed between patients with high and low baseline ANC levels.

[0071] Table 6

[0072]

[0073]

[0074] The present embodiment analyzed the baseline ANC of 71 non-melanoma patients in the second test group, and the baseline ANC cutoff value was determined to be 4.0×10 9 / L, and the patients’ mOS, miPFS, iORR, and DCR were statistically analyzed, as shown in Table 7.

[0075] Table 7

[0076]

[0077] From the results in Table 7, we can see that the low ANC group (ANC≤4.0×10 9 In the cohort of subjects with low ANC (ANC>4.0×10 / L), the mOS was 10.1 months, miPFS was 1.4 months, iORR was 5.7%, and DCR was 34.3%. In contrast, in the high ANC group (ANC>4.0×10 9 In the cohort of subjects with ANC > 4 (ANC > 4), the mOS was 4.2 months, the miPFS was 1.4 months, the iORR was 4.0%, and the DCR was 20%. mOS (HR = 2.6; 95% CI 1.5-4.4), miPFS (HR = 1.4; 95% CI 0.8-2.2), iORR (OR = 0.7; 95% CI 0.1-10.0), DCR (OR = 0.5; 95% CI 0.1-1.7) showed that the prognosis of the high ANC population (ANC> 4) was worse and the response rate was lower. The above results show that the cutoff value of baseline ANC is set at 4.0×10 9 / L, it can accurately predict the best efficacy of OH2 monotherapy in patients with other tumors except melanoma, that is, baseline ANC>4.0×109 / L, the response rate of patients receiving OH2 monotherapy was low, and the baseline ANC was ≤4.0×10 9 When the ANC was ≤4.0×10 / L, the patients had a higher response rate to OH2 monotherapy. 9 Melanoma patients with HBV / L are more likely to benefit from OH2 monotherapy.

[0078] In summary, neutrophils are a key indicator of systemic inflammatory response, and their levels are closely related to tumor development and prognosis. They can be used as a marker to predict the efficacy of OH2 treatment in tumor patients, and the critical value (threshold) for prediction can be 2×10 9 ~5.5×10 9 / L, that is, the efficacy of OH2 treatment in tumor subjects whose baseline ANC level in the blood is below the critical value is significantly better than that in tumor subjects whose baseline ANC level in the blood is above the critical value. Among these critical values, the preferred baseline ANC level critical value range is 3.8×10 9 ~4.1×10 9 / L, the optimal baseline ANC level cutoff value is 4×10 9 / L. In addition, the baseline ANC level is 4×10 9 Tumor patients with low ANC levels below 1 / L are recommended to receive OH2 monotherapy, which has significant efficacy.

[0079] The present application has been described in detail above. Specific examples have been used herein to illustrate the principles and implementation methods of the present application. The description of the above embodiments is intended only to facilitate understanding of the present application and its core concepts. It should be noted that, without departing from the principles of the present application, a number of improvements and modifications may be made to the present application by a person skilled in the art, and such improvements and modifications shall fall within the scope of protection of the claims of the present application.

Claims

1. Application of neutrophil count in predicting the efficacy of oncolytic virus therapy for tumors, characterized in that: The neutrophil count level is the neutrophil count level in the blood of tumor patients before tumor treatment.

2. The use according to claim 1, characterized in that In the application, the oncolytic virus therapy is OH2 oncolytic virus monotherapy.

3. The use according to claim 1, characterized in that In the application, the neutrophil count is used to predict the efficacy of tumor treatment, and the critical value of the neutrophil count for predicting the efficacy of tumor treatment is 2×10 9 ~5.5×10 9 / L; the efficacy of OH2 monotherapy in tumor subjects whose baseline ANC levels in the blood are below the cut-off value is better than that in tumor subjects whose baseline ANC levels in the blood are above the cut-off value.

4. The use according to claim 1, characterized in that In the application, the neutrophil count is used to predict the efficacy of tumor treatment, and the critical value of the neutrophil count for predicting the efficacy of tumor treatment is 3.8×10 9 ~4.1×10 9 / L; the efficacy of OH2 monotherapy in tumor subjects whose baseline ANC levels in the blood are below the cut-off value is better than that in tumor subjects whose baseline ANC levels in the blood are above the cut-off value.

5. The use according to claim 1, characterized in that In the application, the neutrophil count is used to predict the efficacy of tumor treatment, and the critical value of the neutrophil count for predicting the efficacy of tumor treatment is 4.0×10 9 / L; when the baseline ANC level in the blood of cancer patients is 4.0×10 9 The efficacy of OH2 monotherapy in patients with tumors below 4.0×10 / L was better than that in patients with baseline ANC levels above 4.0×10 9 / L tumor subjects receiving OH2 monotherapy.

6. The use according to claim 1, characterized in that In the application, applicable tumor types include at least one of melanoma, colorectal cancer, esophageal cancer, head and neck tumors, gastric cancer, biliary system tumors, and sarcoma.

7. The use according to claim 1, characterized in that In the application, the sample used to detect the neutrophil count level is peripheral blood of a tumor patient.

Images