Patient screening method for oncolytic virus therapy

Abstract

A patient screening method for oncolytic virus therapy, comprising: detecting HLA typing of a patient; and further comprising detecting a tumor antigen expressed by a tumor cell, and / or detecting whether the patient expresses a protein in an antigen presentation pathway.

Description

Screening methods for oncolytic virus therapy patients Technical Field

[0001] This application relates to the field of biomedicine, specifically to a method for screening oncolytic virus treatment populations. Background Technology

[0002] Oncolytic viruses (OVs) are a novel cancer treatment approach. They are a class of natural or recombinant viruses that selectively infect and kill tumor cells without harming normal cells. Unlike traditional chemotherapy and radiotherapy, oncolytic virus therapy has several advantages, including good targeting, fewer adverse reactions, multiple tumor-killing pathways, and low likelihood of developing drug resistance. However, the different tumor types, stages, and heterogeneity pose challenges in selecting suitable patients for OV treatment. Furthermore, patients undergoing oncolytic virus clinical trials often have previously received multiple conventional treatments, which may lead to a weakened immune system and potentially fundamentally altered tumor cells.

[0003] The "Technical Guidelines for the Application of Biomarkers in the Clinical Development of Antitumor Drugs" states that "in the early stages of clinical trials, the use of appropriate biomarkers for exploratory research is encouraged to obtain more information on the effects of drugs on the human body, including pharmacodynamic and toxic effects. Through prospective or retrospective studies on the correlation between biomarkers and clinical outcomes, the efficacy prediction or prognostic value of biomarkers can be explored, providing preliminary basis for the selection of key clinical trial populations, stratification factors, and safety risk control."

[0004] Therefore, an oncolytic virus screening strategy is needed to select suitable patients through specific predictive biomarkers, detect the immune response of patients receiving active treatment, and determine which patients can clinically benefit from oncolytic virus therapy. This would help to maximize treatment efficacy and improve the quality of clinical research.

[0005] Summary of the Invention

[0006] This application provides an oncolytic virus screening strategy that uses HLA typing to screen patients suitable for oncolytic virus therapy. This screening strategy has the following effects: 1) For individuals with specific HLA typing and expressing corresponding tumor antigens, it can significantly promote T cell secretion of IFN-γ and significantly enhance anti-tumor specific T cell responses; 2) It screens out individuals suitable for oncolytic virus therapy, improving treatment effectiveness and accuracy; 3) It is applicable to different oncolytic viruses and has universality.

[0007] This application provides a method for screening patients for oncolytic virus therapy, the method comprising: detecting the patient's HLA typing.

[0008] In one embodiment, the HLA typing is HLA-I type molecules.

[0009] In one embodiment, the HLA typing is HLA-A02.

[0010] In one embodiment, the HLA typing is A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12, or DRB1.

[0011] In one implementation, the A01 classification includes A01:01.

[0012] In one embodiment, the A02 classification includes A02:01, A02:03 and / or A02:07.

[0013] In one embodiment, the A03 classification includes A03:01.

[0014] In one implementation, the A11 classification includes A11:01.

[0015] In one implementation, the A24 classification includes A24:02.

[0016] In one implementation, the A31 classification includes A31:01.

[0017] In one implementation, the DRB1 classification includes DRB1 09:01.

[0018] In one implementation, when the above-mentioned HLA typing is detected in a patient, the patient belongs to the oncolytic virus treatment population.

[0019] In one implementation, an oncolytic virus is administered when the HLA typing described above is detected in a patient.

[0020] In one embodiment, the method includes 1) detecting the patient's HLA typing and 2) detecting tumor antigens expressed by tumor cells.

[0021] In one embodiment, the tumor is a solid tumor.

[0022] In one embodiment, the tumor includes soft tissue sarcoma, head and neck tumors, skin cancer, melanoma, liver cancer, gastric cancer, gynecological and / or genital tumors.

[0023] In one embodiment, the tumor includes synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, hepatocellular carcinoma, and / or gastric cancer.

[0024] In one embodiment, the tumor antigens include MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg, and / or EBV.

[0025] In one implementation, the method includes detecting the following markers:

[0026] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0027] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0028] c) The HLA type is A01, A02, A03:01, A11 and / or A24, and the tumor antigen is PRAME;

[0029] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0030] e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7;

[0031] f) HLA typing is A02, and tumor antigen is HBsAg; and / or

[0032] g) HLA typing of A02, A11, and / or A31, and tumor antigen of EBV. In one embodiment, the method includes detecting the following biomarkers:

[0033] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0034] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0035] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0036] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0037] e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7;

[0038] f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or

[0039] g) HLA typing of A02, A11:01, and / or A31:01, and tumor antigen of EBV. In one embodiment, when the above-mentioned biomarkers are detected in a patient, the patient belongs to the oncolytic virus-preferred treatment population.

[0040] In one implementation, oncolytic virus is administered when the aforementioned markers are detected in a patient.

[0041] In one embodiment, the method further includes detecting the integrity of the antigen presentation pathway.

[0042] In one embodiment, detecting the integrity of the antigen presentation pathway includes detecting whether antigen presentation pathway proteins are expressed, said antigen presentation pathway proteins including antigen processing proteins and / or antigen transport proteins.

[0043] In one embodiment, the protein is selected from one or more of the following group: TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and PSMB10.

[0044] In one embodiment, the method includes 1) detecting the patient's HLA typing, 2) detecting tumor antigens expressed by tumor cells, and 3) detecting the integrity of antigen presentation pathways.

[0045] In one embodiment, the method includes detecting the following biomarkers in a patient, while simultaneously detecting whether proteins of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and / or PSMB10 are expressed in the antigen presentation pathway:

[0046] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0047] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0048] c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME;

[0049] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0050] e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7;

[0051] f) HLA typing is A02, and tumor antigen is HBsAg; and / or

[0052] g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

[0053] In one embodiment, the method includes detecting the following biomarkers in a patient, while simultaneously detecting whether proteins of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and / or PSMB10 are expressed in the antigen presentation pathway:

[0054] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0055] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0056] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0057] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0058] e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7;

[0059] f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or

[0060] g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

[0061] In one implementation, when the aforementioned biomarkers are detected in a patient, the patient is considered to be in the oncolytic virus precision treatment population.

[0062] In one implementation, oncolytic virus is administered when the aforementioned markers are detected in a patient.

[0063] This application also provides a system for predicting oncolytic virus treatment populations, the system including a first module for detecting the patient's HLA typing.

[0064] In one embodiment, the HLA typing is HLA-I type molecules.

[0065] In one embodiment, the HLA typing is HLA-A02 typing.

[0066] In one embodiment, the HLA typing is selected from one or more of the following groups: A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12, and DRB1.

[0067] In one implementation, when the above HLA typing is detected, the patient is predicted to be a candidate for oncolytic virus treatment.

[0068] In one implementation, an oncolytic virus is administered when the HLA typing described above is detected in a patient.

[0069] In one embodiment, the system further includes a second module for detecting tumor cell antigens.

[0070] In one embodiment, the tumor is a solid tumor.

[0071] In one embodiment, the tumor includes soft tissue sarcoma, head and neck tumors, skin cancer, melanoma, liver cancer, gastric cancer, gynecological and / or genital tumors.

[0072] In one embodiment, the tumor includes synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, hepatocellular carcinoma, and / or gastric cancer.

[0073] In one embodiment, the tumor antigens include MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg, and / or EBV.

[0074] In one implementation, when the tumor antigen is detected in a patient, the patient is predicted to be a candidate for oncolytic virus treatment.

[0075] In one implementation, an oncolytic virus is administered when the tumor antigen is detected in a patient.

[0076] In one implementation, the first module and the second module detect the following biomarkers in the patient:

[0077] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0078] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0079] c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME;

[0080] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0081] e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7;

[0082] f) HLA typing is A02, and tumor antigen is HBsAg; and / or

[0083] g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

[0084] In one implementation, the first module and the second module detect the following biomarkers in the patient:

[0085] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0086] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0087] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0088] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0089] e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7;

[0090] f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or

[0091] g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

[0092] In one implementation, when the aforementioned biomarkers are detected in a patient, it is predicted that the patient belongs to the oncolytic virus-preferred treatment population.

[0093] In one implementation, oncolytic virus is administered when the aforementioned markers are detected in a patient.

[0094] In one embodiment, the system further includes a third module for detecting the integrity of the antigen presentation pathway.

[0095] In one embodiment, detecting the integrity of the antigen presentation pathway includes detecting whether antigen processing proteins and / or antigen transport proteins are expressed.

[0096] In one embodiment, the protein is selected from one or more of the following group: TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and PSMB10.

[0097] In one implementation, the first and second modules detect the following biomarkers in the patient, while the third module detects whether proteins of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and / or PSMB10 are expressed in the antigen presentation pathway:

[0098] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0099] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0100] c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME;

[0101] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0102] e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7;

[0103] f) HLA typing is A02, and tumor antigen is HBsAg; and / or

[0104] g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

[0105] In one implementation, the first and second modules detect the following biomarkers in the patient, while the third module detects whether proteins of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and / or PSMB10 are expressed in the antigen presentation pathway:

[0106] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0107] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0108] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0109] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0110] e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7;

[0111] f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or

[0112] g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

[0113] In one implementation, when the aforementioned biomarkers are detected in a patient, the patient is predicted to be a candidate for precision oncolytic virus therapy.

[0114] In one implementation, oncolytic virus is administered when the aforementioned markers are detected in a patient.

[0115] This application also provides an anti-tumor drug delivery platform, which includes an oncolytic virus drug module and a screening module for HLA typing in a patient population.

[0116] In one embodiment, the HLA typing is HLA-I type molecules.

[0117] In one embodiment, the HLA typing is HLA-A02 typing.

[0118] In one embodiment, the HLA typing is selected from one or more of the following groups: A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12, and DRB1.

[0119] In one implementation, when the HLA typing frequency in the patient population is found to be above 40%, the population is considered to be a recipient of oncolytic virus therapy.

[0120] In one implementation, when the HLA typing is found to have a frequency of over 40% in the patient population, oncolytic virus is administered.

[0121] In one embodiment, the screening module further includes screening for tumor antigens expressed by tumor cells.

[0122] In one embodiment, the tumor is a solid tumor.

[0123] In one embodiment, the tumor includes soft tissue sarcoma, head and neck tumors, skin cancer, melanoma, liver cancer, gastric cancer, gynecological and / or genital tumors.

[0124] In one embodiment, the tumor includes synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, hepatocellular carcinoma, and / or gastric cancer.

[0125] In one embodiment, the tumor antigens include MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg, and / or EBV.

[0126] In one implementation, when the tumor antigen expression frequency is found to be above 40%, the population is considered to be a population receiving oncolytic virus treatment.

[0127] In one embodiment, when the tumor antigen expression frequency is found to be above 40%, an oncolytic virus is administered.

[0128] In one implementation, the following biomarkers are screened in the patient population:

[0129] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0130] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0131] c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME;

[0132] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0133] e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7;

[0134] f) HLA typing is A02, and tumor antigen is HBsAg; and / or

[0135] g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

[0136] In one implementation, the following biomarkers are screened in the patient population:

[0137] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0138] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0139] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0140] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0141] e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7;

[0142] f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or

[0143] g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

[0144] In one implementation, when the above-mentioned biomarkers are found to occur more than 40% of the patient population, the population is considered to be a population with a superior oncolytic virus treatment profile.

[0145] In one implementation, oncolytic viruses are used when the aforementioned biomarkers are found to occur at a frequency of more than 40% in the patient population.

[0146] In one embodiment, the screening module further includes screening for whether an antigen-presenting pathway protein is expressed.

[0147] In one embodiment, the antigen presentation pathway proteins include antigen processing proteins and / or antigen transport proteins.

[0148] In one embodiment, the protein is selected from one or more of the following group: TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and PSMB10.

[0149] In one implementation, the following biomarkers are screened in the patient population, while simultaneously screening for expression of the proteins TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and / or PSMB10 in the antigen presentation pathway:

[0150] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0151] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0152] c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME;

[0153] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0154] e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7;

[0155] f) HLA typing is A02, and tumor antigen is HBsAg; and / or

[0156] g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

[0157] In one implementation, the following biomarkers are screened in the patient population, while simultaneously screening for expression of the proteins TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and / or PSMB10 in the antigen presentation pathway:

[0158] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0159] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0160] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0161] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0162] e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7;

[0163] f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or

[0164] g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

[0165] In one implementation, when the above-mentioned biomarkers are found to be expressed at a frequency of more than 40% in the patient population, the population is considered to be a target population for precision oncolytic virus therapy.

[0166] In one implementation, oncolytic viruses are used when the above-mentioned biomarkers are found to be expressed at a frequency of more than 40% in the patient population.

[0167] This application also provides a detection kit comprising a first reagent for detecting the above-mentioned HLA typing, a second reagent for detecting the above-mentioned tumor antigen expression, and / or a third reagent for detecting the integrity of the above-mentioned antigen presentation pathway.

[0168] In one embodiment, the HLA typing is HLA-A02 typing. In another embodiment, the HLA typing is selected from one or more of the following groups: A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12, and DRB1.

[0169] In one embodiment, the tumor antigen includes tumor antigens expressed by synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, lymphoma, hepatocellular carcinoma, and / or gastric cancer. In one embodiment, the tumor antigen includes MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg, and / or EBV.

[0170] In one embodiment, the detection of antigen presentation pathway integrity includes detecting whether the proteins TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9 and / or PSMB10 are expressed in the antigen presentation pathway.

[0171] This application also describes the use of biomarkers in the preparation of oncolytic virus prediction systems and / or antitumor drug screening platforms, said biomarkers including the above-mentioned HLA typing, the above-mentioned tumor antigens and / or the above-mentioned antigen presentation pathway proteins.

[0172] In one embodiment, the HLA typing is HLA-A02 typing. In another embodiment, the HLA typing is selected from one or more of the following groups: A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12, and DRB1.

[0173] In one embodiment, the tumor antigen includes tumor antigens expressed by synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, lymphoma, hepatocellular carcinoma, and / or gastric cancer. In one embodiment, the tumor antigen includes MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg, and / or EBV.

[0174] In one embodiment, the antigen presentation pathway proteins include the detection of whether TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9 and / or PSMB10 proteins are expressed in the antigen presentation pathway.

[0175] The HLA typing, antigen-presenting pathway proteins, and / or tumor antigens described above are used to screen patients for oncolytic virus therapy.

[0176] In one embodiment, the HLA typing is HLA-A02 typing. In another embodiment, the HLA typing is selected from one or more of the following groups: A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12, and DRB1.

[0177] In one embodiment, the tumor antigen includes tumor antigens expressed by synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, lymphoma, hepatocellular carcinoma, and / or gastric cancer. In one embodiment, the tumor antigen includes MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg, and / or EBV.

[0178] In one embodiment, the antigen presentation pathway proteins include the detection of whether TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9 and / or PSMB10 proteins are expressed in the antigen presentation pathway.

[0179] Other aspects and advantages of this application will readily be apparent to those skilled in the art from the detailed description below. Only exemplary embodiments of this application are shown and described in the following detailed description. As will be appreciated by those skilled in the art, the content of this application enables them to make modifications to the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application pertains. Accordingly, the descriptions in the accompanying drawings and specification of this application are merely exemplary and not restrictive. Attached Figure Description

[0180] The specific features of the invention involved in this application are shown in the appended claims. The features and advantages of the invention can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows:

[0181] Figure 1 shows the experiment to validate the HLA screening strategy based on a mouse bladder cancer model. The UNS group did not contain the antigen peptide, the OVA257-264 group had the antigen peptide SIINFEKL added, and KM1 indicated the addition of oncolytic virus.

[0182] Figure 2 shows the experiment to validate the HLA screening strategy based on a mouse melanoma model. The UNS group did not contain the antigen peptide, the Trp2 180-188 group had the antigen peptide SVYDFFVWL added, and KM1 indicated the addition of oncolytic virus.

[0183] Figure 3 shows the experiment validating the HLA screening strategy based on a mouse melanoma model, with PBS as the control group and KM1 as the treatment group. Detailed Implementation

[0184] The following specific embodiments illustrate the implementation of the invention. Those skilled in the art can easily understand other advantages and effects of the invention from the content disclosed in this specification.

[0185] Terminology Definition

[0186] In this application, the term "tumor antigen" refers to a protein or other molecule expressed on or inside tumor cells that can be broken down into multiple antigenic peptides, can be presented by HLA molecules, and activate specific T-cell responses. The terms "presentation" and "subjection" are used interchangeably in this application, referring to the binding between the antigenic peptide and HLA. The term "antigen peptide" refers to a limited number of different peptides produced during the processing of protein antigens in antigen-presenting cells.

[0187] In this application, the terms "T cell response" and "immune response" are used interchangeably and refer to the activation of T cells and / or the induction of one or more effector functions following the binding of a specific HLA-antigen peptide. These effector functions include cytotoxicity, cytokine production, and proliferation.

[0188] In this application, the term "antigen-presenting protein" refers to a protein that performs functions such as processing and transporting antigens during antigen presentation, and includes at least antigen transporters and antigen processing proteins. The term "antigen processing protein" refers to a proteasome that processes antigens into antigenic peptides that facilitate the binding of MHC molecules (also known as HLA molecules), helping cell surface MHC I molecules bind to high-affinity peptides. The antigen processing protein may include, but is not limited to, proteasome subunit β family proteins (PSMB) and TAPBPL, such as PSMB8, PSMB9, or PSMB10. The term "antigen transporter" refers to a protein that can participate in the modification and presentation of endogenous antigenic peptides, usually located on the endoplasmic reticulum, enabling it to bind to MHC class I molecules to form MHC I-antigen peptide complexes, which are then presented to the cell surface for recognition by T cells, generating a specific immune response. The antigen transporter includes, but is not limited to, endoplasmic reticulum aminopeptidase (ERAP) and antigen processing-associated transporters (TAP), such as ERAP1, ERAP2, TAP1, and TAP2.

[0189] In this application, the term "HY-ESO-1" refers to a tumor antigen expressed in various tumors, belonging to the cancer-testis antigen family, whose antigenic peptide can successfully induce a specific CD8+ T lymphocyte immune response. The term "MAGE-A4" refers to a tumor-associated antigen expressed in various tumors, including melanoma, triple-negative breast cancer, non-small cell lung cancer, and esophageal cancer. The term "PRAME" is a member of the cancer / testis antigen (CTA) family; its expression in normal tissues is limited to the testes, ovaries, sebaceous glands, and adrenal glands, while it is highly expressed in various malignant tumors such as melanoma, lung cancer, breast cancer, and esophageal cancer. The term "MART-1" is a tumor-associated antigen highly expressed in melanoma, with low or no expression in normal melanocytes; it belongs to the melanocyte differentiation antigen family and can be recognized by T cells, thereby activating an immune response. The term "gp100" refers to a transmembrane glycoprotein highly expressed in melanocytes and melanoma cells, involved in melanin synthesis and transport, belonging to the melanocyte differentiation antigen category, and can be recognized by T cells, thereby activating an immune response. The term "HPV" refers to human papillomavirus. The HPV genome is divided into three parts: the early gene region (E), the late gene region (L), and the long regulatory region (LCR). E6 and E7 of the early gene region (E) are oncogenes, encoding oncogene proteins that are important factors leading to cervical epithelial carcinogenesis. In one embodiment, the HPV of this application includes HPV 16 / 18 proteins. The term "HBsAg" refers to hepatitis B surface antigen, produced by the integration of cccDNA and HBV DNA fragments from the host genome; it can act as a transcriptional activator of host genes, and the accumulation of HBsAg protein in the endoplasmic reticulum can activate cellular stress pathways. The term "EBV" refers to Epstein-Barr virus-associated antigens, which are a series of proteins expressed during EBV infection. These mainly include EBV nuclear antigen (EBNA), early antigen (EA), membrane antigen (MA), capsid antigen (VCA), and lymphocyte recognition membrane antigen (LYDMA). EBV-infected cells present viral antigens to T cells through HLA molecules. Subsequently, EBV-specific cytotoxic T cells (CTLs) recognize and kill cells expressing EBV antigens.

[0190] In this application, the term "HLA" refers to a group of genes located on human chromosome 6 that encode proteins that can bind to antigenic peptides to form HLA-antigen peptide complexes, presenting tumor antigens to T cells. HLA is divided into HLA class I molecules and HLA class II molecules. Based on allele differences, HLA class I molecules can be further divided into the HLA-A gene family, HLA-B gene family, and HLA-C gene family, while HLA class II molecules can be divided into the HLA-DR gene family, HLA-DQ gene family, and HLA-DP gene family.

[0191] In this application, "immunotherapy" refers to treating a disease or condition by inducing or enhancing an immune response in an individual. In some embodiments, immunotherapy refers to a therapy that includes administering one or more drugs to an individual to elicit a T-cell response.

[0192] In this application, "treatment population" refers to a patient population screened for a specific HLA subtype. "Advantageous treatment population" refers to a patient population screened for a specific HLA subtype and tumor antigen. "Precision treatment population" refers to a patient population screened for a specific HLA subtype, tumor antigen, and antigen-presenting pathway protein. Compared to no oncolytic virus therapy, oncolytic virus therapy significantly activates tumor-specific T-cell responses in patient populations. In some embodiments, tumor-specific T-cell responses in the treatment population, advantageous treatment population, or precision treatment population screened using this application are activated to approximately 1, 2, 3, 4, or 5 times the original level (i.e., the unscreened patient population).

[0193] In this application, the term "oncolytic virus" refers to a natural or recombinant virus capable of selectively infecting and killing tumor cells without harming normal cells. The oncolytic viruses include, but are not limited to, adenovirus (AdV), herpes simplex virus (HSV), Newcastle disease virus (NDV), measles virus (MV), vesicular stomatitis virus (VSV), poliovirus, Coxsackie virus, reovirus, and vaccinia virus (VV). The oncolytic viruses of this application can also be used in combination with immune checkpoint inhibitors, such as PD-L1 / PD-L2 inhibitors. In one embodiment, the oncolytic viruses of this application can be used in combination with a PD-1 antibody, wherein the PD-1 antibody can be any known PD-1 antibody. This combination can be administered simultaneously with an immune checkpoint inhibitor or separately from the immune checkpoint inhibitor.

[0194] In this application, the term "about" means ±50% of the corresponding value.

[0195] Invention Details

[0196] On the one hand, this disclosure provides a method for screening a patient population for oncolytic virus therapy, the method comprising: detecting the patient's HLA typing, detecting antigen expression in tumor cells and / or detecting the integrity of antigen presentation pathways.

[0197] HLA

[0198] In antigen-presenting cells (APCs), protein antigens are processed into peptides. These peptides bind to HLA and are presented as peptide-HLA complexes to the cell surface of T cells. Different individuals express different HLA molecules, and different HLA molecules present different peptides. Therefore, according to the prior art, if a peptide or fragment of a larger polypeptide is presented by an HLA molecule expressed by a subject, it is identified as immunogenic to that specific human subject. In other words, the prior art describes immunogenic peptides as HLA-restricted epitopes. However, HLA-restricted epitopes induce T cell responses only in a subset of individuals expressing HLA molecules. Despite HLA allele matching, a peptide that activates a T cell response in one individual may be inactive in others. Therefore, it is unknown how an individual's HLA molecules present antigen-derived epitopes that positively activate a T cell response.

[0199] HLA is encoded by most polymorphic genes in the human genome. Each person possesses three HLA class I molecules (HLA-A*, HLA-B*, HLA-C*) and four HLA class II molecules (HLA-DP*, HLA-DQ*, HLA-DRB1*, HLA-DRB3* / 4* / 5*), which present different epitopes from the same protein antigen. The function of HLA molecules is to regulate T cell responses. However, how human HLA regulates T cell activation remains unknown.

[0200] The nomenclature used to represent the amino acid sequence of an HLA molecule is as follows: Gene Name * Allele: Protein Number, for example, it could look like: HLA-A*02:25. In this example, "02" refers to the allele. In this application, it can also be written as HLA-A02 or HLA-A2. In most cases, the allele is defined by serotype C, meaning that proteins of a given allele will not react with each other in serological assays. Protein numbers are assigned sequentially upon protein discovery. Any protein with a different amino acid sequence is assigned a new protein number (e.g., even a change in one amino acid in the sequence is considered a different protein number). Further information about the nucleic acid sequence of a given locus can be appended to the HLA nomenclature, but such information is not required for the methods described herein.

[0201] The mouse major histocompatibility complex (MHC) and the human MHC (HLA) share a high degree of structural and functional similarity. Immunologically, both activate T cells by recognizing and presenting antigen fragments. Structurally, MHC molecules consist of heavy and light chains forming antigen-binding grooves for loading and presenting antigen fragments to T cells. Regarding antigen presentation mechanisms, MHC molecules participate in antigen presentation in both humans and mice. Class I molecules are responsible for presenting intracellular pathogen antigen fragments, while class II molecules primarily present extracellular antigens; this mechanism is conserved across species. The properties of MHC genes are also highly similar. The MHC gene complex consists of multiple closely adjacent gene loci whose encoded products have the same or similar functions. This polymorphism and polygenicity are present in both the mouse MHC (H-2 complex) and the human HLA system.

[0202] According to the embodiments provided in this application, oncolytic viruses promote the presentation function of HLA and significantly enhance tumor-specific T cell responses. Therefore, when a patient is found to have a specific HLA that matches the tumor antigen, the administration of oncolytic viruses can promote its antigen presentation function, thereby enhancing the immune response.

[0203] Tumor antigens

[0204] Based on the examples provided in this application, oncolytic viruses can activate HLA to present tumor antigens, thereby activating tumor-specific T cell responses. Therefore, the tumor antigens described in this application include any tumor antigens currently known.

[0205] In one embodiment, the tumor is a solid tumor.

[0206] In one embodiment, the tumor includes soft tissue sarcoma, head and neck tumors, skin cancer, melanoma, liver cancer, gastric cancer, gynecological and / or genital tumors.

[0207] In one embodiment, the tumor includes synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, hepatocellular carcinoma, and / or gastric cancer.

[0208] The tumor antigens described in this application can be presented by HLA, including but not limited to the following tumor antigens:

[0209] A)NY-ESO-1

[0210] NY-ESO-1 (New York Esophageal Squamous Cell Carcinoma 1) is an antigen expressed in various tumors and belongs to the cancer testis antigen family. It is an important target in tumor immunotherapy because it is immunogenic and can induce an immune response in the body.

[0211] NY-ESO-1 can be presented by multiple HLA alleles, among which the HLA-A2 allele is the most studied. Certain peptides of NY-ESO-1, especially the NY-ESO-1(157-165) peptide, are HLA-A02 epitopes with immunogenicity and strong immunogenicity. This means that the NY-ESO-1(157-165) peptide can be presented to T cells by HLA-A02 molecules, thereby activating an immune response against tumor cells expressing NY-ESO-1 (Liu Jingwei et al., Journal of Peking University (Health Sciences), 2017, 49(5):840-846.).

[0212] Besides HLA-A2, there are other restrictive HLA alleles for the NY-ESO-1 antigen. For example, HLA-A11 is also a restrictive allele of NY-ESO-1. Wang Jie et al. (Abstracts of the 13th National Congress of Immunology, 2018) screened for HLA-A11 restrictive epitopes of the NY-ESO-1 antigen in order to provide more options for NY-ESO-1 antigen-based tumor cell therapy.

[0213] Studies by Jager E et al. have shown that NY-ESO-1 can be presented by the HLA-B51 allele and can activate CD8+ T cell responses (Cancer Immun, 2002, 19(2):12.). Furthermore, other studies have shown that NY-ESO-1 can be presented by the HLA-DRB4 allele and can activate CD4+ T cell responses. This indicates that NY-ESO-1 can activate CD8+ T cells not only through the HLA-A02 allele but also through the HLA-DRB4 allele, thereby enhancing the body's immune response. (Jager E et al., J Exp Med, 2000, 191(4):625-630.)

[0214] In summary, NY-ESO-1 can be presented through multiple HLA alleles, including but not limited to HLA-A02, HLA-A11, HLA-A24, HLA-A31, HLA-A68, HLA-B07, HLA-B35, HLA-B51, HLA-B52, and HLA-C12, which makes it a promising candidate for tumor immunotherapy.

[0215] B)MAGE-A4

[0216] MAGE-A4 (melanoma-associated antigen A4) is a tumor antigen expressed in a variety of solid tumors and belongs to the MAGE protein family. In normal tissues, MAGE-A4 is usually expressed only in immune-exempt sites such as the testes, but it is expressed in a variety of tumors, such as synovial sarcoma, non-small cell lung cancer, head and neck squamous cell carcinoma, ovarian cancer, urothelial carcinoma, melanoma, and gastroesophageal cancer.

[0217] MAGE-A4 antigen can be broken down into multiple antigenic peptides that can be presented by HLA molecules and activate specific T cell responses. In tumor immunotherapy, several HLA-A02-restricted MAGE-A4 antigenic peptides have been identified that can activate CD8+ T cells, thereby producing a killing effect on tumor cells. For example, MAGE-A4102-130 (MLP-1), MAGE-A4134-160 (MLP-2), MAGE-A4230-239 peptide antigenic epitopes GVYDGREHTV, and MAGE-A4274-306 (MLP-3) are potential long peptides targeting the MAGE-A4 antigen. They have shown strong immunogenicity in in vitro experiments and can activate T cells (Lanqi Cen et al., Cancer Cell International, volume 24, Article number: 232 (2024)).

[0218] In addition, MAGE-A4 is not only presented by HLA-A02, but can also be presented by HLA-A01 and HLA-A24 alleles, and can activate the corresponding T cell response (Akiyama Y et al., Cancer Immunol Immunother, 2012, 61(12):2311-2319.).

[0219] C)PRAME

[0220] PRAME (preferentially expressed antigen in melanoma) is a tumor-associated antigen expressed in a variety of tumors, but its expression level is low or absent in healthy tissues, making it an attractive target for immunotherapy. PRAME can be presented by a variety of HLA-A1 alleles, including but not limited to HLA-A*02:01, HLA-A*01:01, HLA-A*03:01, HLA-A*24:02, and HLA-A*11:01 (Richard Addo et al., Blood, 2020, 136 (Supplement 1)).

[0221] D)MART-1

[0222] MART-1 (melanoma antigen 1) is a tumor-associated antigen expressed in melanoma and several other tumor types. It is an important target for immunotherapy because it can be presented by specific HLA alleles, thereby activating the T-cell immune response against tumor cells.

[0223] MART-1 can be presented by the HLA-A02 (HLA-A*0201) allele. In one study, clinical benefits have been observed in some patients by adoptive transfer of lymphocytes expressing high-affinity T-cell receptors (TCRs) that specifically target the MART-1 27-35 / HLA-A*0201 complex. This suggests that specific peptides of MART-1 (such as the 27-35 peptide) can bind to the HLA-A*0201 molecule and form peptide-MHC complexes on the surface of melanoma cells. These complexes can be recognized by T-cell receptors and activate T cells to kill tumor cells (Ali R. Jazirehi et al., Cancer Res (2011) 71(4):1406–1417.).

[0224] In addition, MART-1 can bind to other HLA alleles, such as, but not limited to, HLA-A03 (HLA-A*0301), HLA-A11, HLA-A24, HLA-A32, HLA-A68, HLA-B07, HLA-B35, and HLA-B45, to present different MART-1 peptides.

[0225] E)gp100

[0226] gp100 (melanoma-associated antigen) is a lineage antigen expressed in melanocytes and melanomas. It can be presented to T cells via specific HLA alleles, thereby activating an immune response against tumor cells. gp100 can be presented by the HLA-A02 (HLA-A*02:01) allele (Chen Yuan et al., Abstracts of the 14th National Congress of Immunology, 2021). In addition, gp100 can bind to other HLA alleles, including but not limited to HLA-A03 (HLA-A*0301), HLA-A11, HLA-A24, HLA-A32, HLA-A68, HLA-B07, HLA-B35, and HLA-B45, presenting different MART-1 peptides.

[0227] F)HPV E6 / E7

[0228] HPV (human papillomavirus) E6 and E7 proteins are viral proteins closely related to the development of malignant tumors such as cervical cancer. They promote malignant transformation of cells by interfering with cell cycle regulation. E6 and E7 proteins can be presented by various HLA alleles, thereby activating specific T-cell immune responses. HPV E6 and E7 proteins can be presented by HLA-A2 and HLA-A11 alleles, resulting in a strong HLA-A2 and HLA-A11-restricted HPV18E7-specific CD8+ T-cell immune response (Shiwen Peng et al., Journal of Biomedical Science, volume 29, Article number: 80 (2022)). HPV E6 / E7 proteins can also be presented by HLA class II molecules, such as HLA-DRB1 (DRB1 09:01).

[0229] G)HBsAg

[0230] Hepatitis B surface antigen (HBsAg) is a hepatitis B virus (HBV) surface antigen. It can be degraded into polypeptide fragments by the proteasome, which then bind to HLA molecules and are ultimately presented to CD8+ T cells. HBsAg also regulates cell production and influences the reconstruction of the host immune system through direct interaction with human monocytes and macrophages via HLA molecule presentation. It can be presented by HLA-A02 typing, including but not limited to A02:01, A02:03, and A02:07.

[0231] H)EBV

[0232] EBV antigens are antigens produced by host cells after infection with Epstein-Barr virus. Most infected individuals retain EBV throughout their lives, and problems are generally rare. However, in certain cases, EBV is associated with the development of some cancers, including Burkitt's lymphoma, Hodgkin's lymphoma, EBV-positive post-transplant lymphoproliferative disease (PTLD), gastric cancer, and nasopharyngeal carcinoma. For example, LMP1 and LMP2 are latent membrane proteins of EBV and are expressed by most nasopharyngeal carcinoma cells (Nancy Raab-Traub, Semin Cancer Biol, 2002, 12(6):431-441). EBV antigens can be presented to T cells by HLA class I molecules, thereby triggering an EBV-specific T cell response. HLA class I molecules include, but are not limited to, HLA-A02, HLA-A11 (HLA-A11:01), and HLA-A31 (HLA-A31:01).

[0233] Based on existing research on tumor antigens and their corresponding restrictive HLA types, and the experimentally demonstrated principle that oncolytic viruses can promote HLA presentation, this indicates that any tumor antigen capable of HLA presentation can have its presentation function enhanced through oncolytic virus treatment, thereby strengthening tumor-specific T-cell responses. Therefore, any known HLA-presentable tumor antigen is applicable to this application.

[0234] Antigen presentation pathway integrity

[0235] Antigen presentation is a crucial process by which the immune system recognizes and responds to endogenous and exogenous antigens (such as viral antigens or tumor antigens). This process involves multiple steps, including antigen uptake, processing, peptide synthesis, peptide binding to MHC molecules, and finally, presentation to T cells on the cell surface. Therefore, the integrity of the antigen presentation pathway affects HLA-presented antigens. This application demonstrates pathway integrity by detecting the expression of key genes / proteins in the antigen presentation pathway.

[0236] In the process of antigen presentation, genes / proteins such as TAPBP (Tapasin), PSMB8, PSMB9, PSMB10, ERAP1 (Endoplasmic Reticulum Aminopeptidase 1), ERAP2 (Endoplasmic Reticulum Aminopeptidase 2), TAP1 (Transporter associated with antigen processing 1), and TAP2 (Transporter associated with antigen processing 2) all play crucial roles. They are indispensable in ensuring that antigens can be effectively processed by cells and presented to T cells.

[0237] TAP1 and TAP2 are key transport proteins in antigen processing and presentation. They form heterodimers responsible for transporting cytoplasmic peptides to the endoplasmic reticulum (ER) so that these peptides can bind to MHC class I molecules. TAPs are essential for maintaining the stability of MHC class I molecules and presenting antigen peptides to CD8+ T cells. TAPBPL is a molecular chaperone in the ER that facilitates the binding of MHC class I molecules to antigen peptides and is crucial for the proper folding and stable expression of MHC class I molecules on the cell surface. PSMB8, PSMB9, and PSMB10 are catalytic subunits of the immunoproteasome. Under the induction of cytokines such as interferon-γ (IFN-γ), they replace the corresponding subunits in the standard proteasome to form the immunoproteasome. The immunoproteasome is more efficient in processing antigen peptides, generating peptides more suitable for binding to MHC class I molecules, thereby enhancing antigen presentation. ERAP1 and ERAP2 are endoplasmic reticulum aminopeptidases that are responsible for pruning the N-terminal amino acids of antigenic peptides to ensure that the peptide length and sequence are suitable for the binding groove of MHC class I molecules.

[0238] Dysfunction or loss of these proteins can lead to reduced antigen presentation efficiency, affecting T cell recognition of antigens and thus weakening the body's immune response. For example, loss of function of TAP1 and TAP2 can result in reduced expression of MHC class I molecules, interfering with the formation of cytotoxic T lymphocytes and affecting immune responses to certain pathogens (Ian Mantel et al., Nature reviews. Clinical oncology, 2022 Jan 11.). Therefore, these proteins are indispensable in antigen presentation pathways.

[0239] Oncolytic virus

[0240] According to the embodiments provided in this application, regardless of the type of oncolytic virus used or whether the oncolytic virus is genetically modified, it will promote the HLA presentation function. Therefore, the oncolytic virus used in this application can be any known oncolytic virus, such as including but not limited to adenovirus (AdV), herpes simplex virus (HSV), Newcastle disease virus (NDV), measles virus (MV), vesicular stomatitis virus (VSV), poliovirus, Coxsackie virus, reovirus and vaccinia virus (VV).

[0241] In one embodiment, the oncolytic virus of this application can also be used in combination with an immune checkpoint inhibitor, such as a PD-L1 / PD-L2 inhibitor. In one embodiment, the oncolytic virus of this application can be used in combination with a PD-1 antibody, wherein the PD-1 antibody can be any known PD-1 antibody. The combination can be administered simultaneously with an immune checkpoint inhibitor or separately from the immune checkpoint inhibitor.

[0242] Filtering methods

[0243] This application involves detecting the patient's HLA typing, tumor antigens expressed in tumor cells, and / or antigen-presenting pathway proteins.

[0244] HLA testing methods can be any known testing method in the field, including but not limited to polymerase chain reaction-sequence-specific primers (PCR-SSP), polymerase chain reaction-sequence-specific oligonucleotide hybridization (PCR-SSO), sequence-based genotyping (SBT), restriction fragment length polymorphism analysis (PCR-RFLP), polymerase chain reaction single-strand conformation polymorphism analysis (PCR-SSCP), specific primer PCR technology (PCR-SSP), liquid phase DNA probe hybridization capture technology, next-generation gene sequencing methods, and Luminex screening.

[0245] In one implementation, this application detects HLA using next-generation sequencing.

[0246] The detection method for tumor antigens can be any known detection method in the field, including but not limited to whole exome sequencing (WES), RNA sequencing (RNA-seq), mass spectrometry, immunohistochemistry (IHC), flow cytometry, ELISPOT (enzyme-linked immunospot assay), TCR sequencing, NEST technology platform, SABAs system, Presenter system, RootPath system and MHTEM system.

[0247] In one embodiment, this application uses immunohistochemistry to detect the expression of tumor antigens.

[0248] The detection method for antigen presentation pathway proteins can be any known detection method in the art, including but not limited to Western blotting (WB), immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), flow cytometry, mass spectrometry, pMHC multimer staining, gene sequencing, and detection of abnormal glycan glycoproteins (TAP).

[0249] In one embodiment, this application detects antigen presentation pathway proteins by gene sequencing.

[0250] In one implementation, when the HLA typing is detected as A02, the individual belongs to the oncolytic virus treatment population.

[0251] In one implementation, when the HLA type is detected as A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12 and / or DRB1, the individual belongs to the oncolytic virus treatment population.

[0252] For example, the A01 subtype includes A01:01. For example, the A02 subtype includes A02:01, A02:03, and / or A02:07. For example, the A03 subtype includes A03:01. For example, the A11 subtype includes A11:01. For example, the A24 subtype includes A24:02. For example, the A31 subtype includes A31:01. For example, the DRB1 subtype includes DRB1 09:01.

[0253] In one implementation, patients are considered to be in a predisposing population for oncolytic virus therapy when the following biomarkers are detected in their blood:

[0254] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0255] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0256] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0257] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0258] e) HLA typing is A02:01, A11:01 and / or DRB1, and tumor antigen is HPV E6 / E7;

[0259] f) HLA typing is A02, and tumor antigen is HBsAg; and / or

[0260] g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

[0261] In one implementation, if the following biomarkers are detected, along with the detection of protein expression of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and / or PSMB10 in the antigen presentation pathway, then the patient belongs to the oncolytic virus precision therapy population:

[0262] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0263] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0264] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0265] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0266] e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7;

[0267] f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or

[0268] g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

[0269] system

[0270] This application provides a system comprising a first module for detecting a patient's HLA typing, a second module for detecting tumor antigens, and / or a third module for detecting the integrity of antigen presentation pathways. The first module can detect patient HLA using any known method, including but not limited to polymerase chain reaction-sequence-specific primers (PCR-SSP), polymerase chain reaction-sequence-specific oligonucleotide hybridization (PCR-SSO), sequence-based genotyping (SBT), restriction fragment length polymorphism analysis (PCR-RFLP), polymerase chain reaction-single strand conformation polymorphism analysis (PCR-SSCP), specific primer PCR technology (PCR-SSP), liquid-phase DNA probe hybridization capture technology, next-generation sequencing (NGS) based methods, and Luminex screening. The second module can detect tumor antigen expression using any known method, including but not limited to whole-exome sequencing (WES), RNA sequencing (RNA-seq), mass spectrometry, immunohistochemistry (IHC), flow cytometry, ELISPOT (enzyme-linked immunospot assay), TCR sequencing, the NEST technology platform, SABAs system, Presenter system, RootPath system, and MHTEM system. The third module can detect the integrity of antigen presentation pathways using any known method, including but not limited to Western blotting (WB), immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), flow cytometry, mass spectrometry, pMHC multimer staining, and detection of abnormal glycan glycoproteins (TAP).

[0271] The first, second, and third modules in the system described in this application can be run in any order. For example, the first module can be run first, followed by the second module, and finally the third module. Alternatively, the first module can be run first, followed by the third module, and finally the second module.

[0272] The system described in this application may further include a storage module configured to store data on the class I and / or class II HLA genotypes of each subject in a model population including patients, and the amino acid sequences of one or more test peptides; wherein the aforementioned model population represents the target human population for testing.

[0273] The system described in this application may further include a computing module configured to identify and / or quantify the amino acid sequences of multiple class I HLA molecules in one or more test peptides that can bind to each subject in the aforementioned model population and / or the amino acid sequences of multiple class II HLA molecules in one or more test peptides that can bind to each subject in the aforementioned model population.

[0274] The system described in this application may further include a data analysis and interpretation module. This data analysis and interpretation module can submit HLA alleles in batches, and it may include any known analysis software for processing, such as TypeLoader2.

[0275] The system described in this application may also include a report generation module, wherein the report may include a detailed description of HLA alleles, matching suggestions, etc.

[0276] The system described in this application may also include an output module configured to display the values ​​of any output predictions or treatment options or recommendations described herein, or any pharmacodynamic biomarkers described herein.

[0277] In one implementation, when the system detects that a patient's HLA type is HLA-I, it outputs that the patient is a candidate for oncolytic virus treatment.

[0278] In one implementation, when the system detects that a patient's HLA type is HLA-A02, it outputs that the patient is a candidate for oncolytic virus treatment.

[0279] In one implementation, when the system detects that a patient's HLA type is A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12, and / or DRB1, it outputs that the patient is a recipient of oncolytic virus therapy, wherein the A01 type includes A01:01, the A02 type includes A02:01, A02:03, and / or A02:07, the A11 type includes A11:01, the A03 type includes A03:01, the A24 type includes A24:02, the A31 type includes A31:01, and the DRB1 type includes DRB1:09:01.

[0280] In one implementation, when the system detects tumor antigens expressed by solid tumor cells, it outputs that the patient is a recipient of oncolytic virus treatment.

[0281] In one implementation, when the system detects tumor antigens expressed by cells of soft tissue sarcoma, head and neck tumors, skin cancer, melanoma, liver cancer, gastric cancer, gynecological and / or genital tumors, it outputs that the patient is a population for oncolytic virus treatment.

[0282] In one implementation, when the system detects tumor antigens expressed by synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer cells, hepatocellular carcinoma, and / or gastric cancer, the patient is identified as a candidate for oncolytic virus treatment.

[0283] In one implementation, when the system detects that the tumor antigens expressed by the tumor cells are MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg and / or EBV, the system outputs that the patient is a population receiving oncolytic virus treatment.

[0284] In one implementation, a patient is considered to be in a predisposing population for oncolytic virus therapy when the system simultaneously detects the following biomarkers:

[0285] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0286] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0287] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0288] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0289] e) HLA typing is A02:01, A11:01 and / or DRB1, and tumor antigen is HPV E6 / E7;

[0290] f) HLA typing is A02, and tumor antigen is HBsAg; and / or

[0291] g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

[0292] In one implementation, when the system detects the following biomarkers, and also detects protein expression of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and / or PSMB10 in the antigen presentation pathway, then the patient belongs to the oncolytic virus precision therapy population:

[0293] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0294] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0295] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0296] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0297] e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7;

[0298] f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or

[0299] g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

[0300] platform

[0301] On the other hand, this application also provides an anti-tumor drug delivery platform, which includes an oncolytic virus drug module and a screening module for HLA typing in a patient population. The drug delivery platform provided by this application can screen for patient populations with specific HLA alleles, thereby improving the targeting and effectiveness of oncolytic virus therapy.

[0302] In one implementation, when the platform detects that a patient's HLA type is HLA-I and the distribution frequency of this HLA type is more than 40%, the platform determines that the patient population is a population undergoing oncolytic virus treatment.

[0303] In one embodiment, when the platform detects that a patient's HLA type is HLA-A02 and the distribution frequency of this HLA type is more than 40%, the platform determines that the patient population is a population undergoing oncolytic virus treatment.

[0304] In one implementation, when the platform detects that a patient's HLA type is A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12, and / or DRB1, and the distribution frequency of this HLA type is greater than 40%, the platform determines that the patient population is a population undergoing oncolytic virus treatment. Wherein, the A01 type includes A01:01, the A02 type includes A02:01, A02:03, and / or A02:07, the A11 type includes A11:01, the A03 type includes A03:01, the A24 type includes A24:02, the A31 type includes A31:01, and the DRB1 type includes DRB1:09:01.

[0305] In one embodiment, the screening module further includes screening for tumor antigens expressed by tumor cells.

[0306] In one implementation, when the platform screens for tumor antigens expressed by solid tumor cells, the patient population is determined to be a population undergoing oncolytic virus treatment.

[0307] In one implementation, when the platform screens for tumor antigens expressed by cells of soft tissue sarcoma, head and neck tumors, skin cancer, melanoma, liver cancer, gastric cancer, gynecological and / or genital tumors, the patient population is determined to be a population for oncolytic virus treatment.

[0308] In one implementation, when the platform screens for tumor antigens expressed by synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer cells, hepatocellular carcinoma, and / or gastric cancer, the patient population is determined to be a population for oncolytic virus treatment.

[0309] In one embodiment, when the platform screens for tumor antigens expressed on the surface of tumor cells such as MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg, and / or EBV, the patient population is determined to be a population for oncolytic virus treatment.

[0310] In one implementation, when the platform simultaneously identifies patients with the following biomarkers, and their expression frequency is above 40%, the patient population is determined to be a population with a favorable response to oncolytic virus therapy:

[0311] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0312] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0313] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0314] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0315] e) HLA typing is A02:01, A11:01 and / or DRB1, and tumor antigen is HPV E6 / E7;

[0316] f) HLA typing is A02, and tumor antigen is HBsAg; and / or

[0317] g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

[0318] In one embodiment, the screening module further includes screening whether antigen-presenting pathway proteins are expressed.

[0319] In one implementation, when the platform screens for the following biomarkers, it also screens for the protein expression of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and / or PSMB10 in the antigen presentation pathway, and the expression frequency is above 40%, then the patient population is determined to be a population for precision oncolytic virus therapy:

[0320] a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4;

[0321] b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1;

[0322] c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME;

[0323] d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100;

[0324] e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7;

[0325] f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or

[0326] g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

[0327] It is known in the art that if a specific HLA allele has a distribution frequency of over 40% in a patient population, it means that the allele is relatively common in that patient population and may be associated with the occurrence, development, or response to a specific treatment. Such distribution frequencies can provide important information for clinical trial design, patient stratification, and personalized treatment. Therefore, by screening for patient populations with specific HLA alleles, the targeting and effectiveness of treatment can be improved.

[0328] Without being limited by any theory, the embodiments described below are merely for illustrating the various technical solutions of the present invention and are not intended to limit the scope of the present invention.

[0329] Example

[0330] Example 1: Clinical Screening Strategy

[0331] Blood and tumor tissue samples were collected from the patient. Based on the patient's indication, HLA typing, antigen presentation, and tumor cell expression antigen biomarkers were tested according to Table 1. If all three results met the requirements, the patient was successfully screened and belonged to the oncolytic virus treatment population.

[0332] Table 1. Screening biomarkers for oncolytic virus indications

[0333] Example 1.1 HLA typing detection method

[0334] HLA testing methods can be any known testing method in the field, including but not limited to polymerase chain reaction-sequence-specific primers (PCR-SSP), polymerase chain reaction-sequence-specific oligonucleotide hybridization (PCR-SSO), sequence-based genotyping (SBT), restriction fragment length polymorphism analysis (PCR-RFLP), polymerase chain reaction single-strand conformation polymorphism analysis (PCR-SSCP), specific primer PCR technology (PCR-SSP), liquid phase DNA probe hybridization capture technology, next-generation gene sequencing methods, and Luminex screening.

[0335] Description of the method for detecting antigen-presenting pathway protein genes using next-generation sequencing: Blood is collected from the patient, DNA is extracted, PCR amplification is performed, sequencing is conducted, and data analysis is performed.

[0336] Example 1.2 Method for detecting tumor cell expression antigens

[0337] The detection method for tumor antigens can be any known detection method in the field, including but not limited to whole exome sequencing (WES), RNA sequencing (RNA-seq), mass spectrometry, immunohistochemistry (IHC), flow cytometry, ELISPOT (enzyme-linked immunospot assay), TCR sequencing, NEST technology platform, SABAs system, Presenter system, RootPath system and MHTEM system.

[0338] Description of the method for detecting tumor antigen expression using immunohistochemistry: Tumor tissue from the patient is collected, paraffin sections are prepared, and immunohistochemical staining is performed on a fully automated immunohistochemical analyzer using MAGE-A4 antibody, PRAME antibody, NY-ESO-1 antibody, HPV E6 / E7 antibody, MART-1 antibody, gp100 antibody, HBsAg antibody, and / or EBV antibody. The quality of the stained sections will be reviewed; unsatisfactory stained sections will be re-stained according to the pathologist's assessment. Results for acceptable stained sections are interpreted and recorded.

[0339] Example 1.3 Method for detecting the integrity of antigen presentation pathway

[0340] The detection method for antigen presentation pathway proteins can be any known detection method in the art, including but not limited to Western blotting (WB), immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), flow cytometry, mass spectrometry, pMHC multimer staining, gene sequencing, and detection of abnormal glycan glycoproteins (TAP).

[0341] Description of the method for detecting antigen-presenting pathway protein genes using next-generation sequencing: Blood is collected from the patient, DNA is extracted, PCR amplification is performed, sequencing is conducted, and data analysis is performed.

[0342] Example 2: Validating the HLA screening strategy based on a mouse bladder cancer model

[0343] A cell line expressing the OVA antigen, MB49-OVA, was established using mouse bladder cancer cells MB49 (Dr. Longcheng Li, Laboratory of Molecular Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China). MB49-OVA tumors were then established in C57BL / 6 mice. When the tumor volume reached 100 mm^3, intratumoral injection of KM1 was performed. KM1 is a recombinant vaccinia virus developed by Shenzhen Huayao Kangming Biopharmaceutical Co., Ltd., which uses Listeria vaccinia virus strain as a vector for genomic modification, deleting the TK, L025, and A46R genes and inserting the 4-1BBL and IL-21 genes. It is deposited at the China Center for Type Culture Collection (CCTCC) with accession number V201938, dated July 4, 2019; the strain name is genetically modified Listeria genotype vaccinia virus KM1, and the depositor is Shenzhen Huayao Kangming Biopharmaceutical Co., Ltd. Limited Liability Company (Applicant). Ten days after KM1 injection, mice were sacrificed, and spleen cells were isolated. Mouse spleen cells were cultured in 96-well plates, and the antigenic peptide OVA (257-264) (SIINFEKL) (Sangon Biotech (Shanghai) Co., Ltd.) was added during the culture process. IFN-γ was measured in the cell culture medium after 48 hours. The results are shown in Figure 1. After adding OVA257-264, the IFN-γ secretion level of spleen cells in the MB49-OVA+KM1 group was significantly increased (approximately 3-fold) compared to the MB49-OVA group; compared to the MB49-OVA+KM1 group without the antigenic peptide, the IFN-γ secretion level increased nearly 7-fold after adding the antigenic peptide. These results indicate that the oncolytic virus effectively promoted a specific T-cell response to the MHC H2b-presented OVA257-264 antigenic peptide (SIINFEKL).

[0344] Example 3: Validating the HLA screening strategy based on a mouse melanoma model

[0345] A cell line expressing the endogenous tumor antigen Trp2 was established using mouse melanoma cells B16F10 (Shanghai Jiao Tong University School of Medicine). B16F10 tumors were then created in C57BL / 6 mice. When the tumor volume reached 100 mm³, KM1 was injected intratumorally. Ten days after KM1 injection, mice were sacrificed, and spleen cells were isolated. Mouse spleen cells were cultured in 96-well plates, with the Trp2 antigen peptide Trp2(180-188) (SVYDFFVWL) (Sangon Biotech (Shanghai) Co., Ltd.) added during the culture process. After 48 hours, the cell culture medium was collected to measure IFN-γ. As shown in Figure 2, after the addition of Trp2 (180-188), the IFN-γ secretion level of spleen cells in the B16F10+KM1 group was significantly increased compared to the B16F10 group. These results indicate that the oncolytic virus effectively promotes the specific T cell response against Trp2 180-188 (SVYDFFVWL) presented by MHC H2b. In Figure 3, the spleen volume of the animals in the KM1 group was larger than that in the PBS group, indicating that KM1 can effectively activate the immune response, causing immune cell proliferation and resulting in spleen enlargement.

[0346] The foregoing detailed description is provided by way of explanation and example and is not intended to limit the scope of the appended claims. Various variations of the embodiments listed herein will be apparent to those skilled in the art and are reserved within the scope of the appended claims and their equivalents.

Claims

1. A method for screening a population for oncolytic virus treatment, the method comprising: The patient's HLA typing was performed.

2. The method according to claim 1, wherein the HLA typing is HLA-I type molecule.

3. The method according to claim 1, wherein the HLA typing is HLA-A02.

4. The method according to claim 1, wherein the HLA typing is A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12 typing and / or DRB1.

5. The method according to claim 4, wherein the A01 classification includes A01:

01.

6. The method according to claim 4, wherein the A02 classification includes A02:01, A02:03 and / or A02:

07.

7. The method according to claim 4, wherein the A03 classification includes A03:

01.

8. The method according to claim 4, wherein the A11 classification includes A11:

01.

9. The method according to claim 4, wherein the A24 subtype includes A24:

02.

10. The method according to claim 4, wherein the A31 subtype includes A31:

01.

11. The method according to claim 4, wherein the DRB1 classification includes DRB1 09:

01.

12. The method according to any one of claims 1-11, wherein when the HLA typing of any one of claims 1-11 is detected in a patient, the patient belongs to the oncolytic virus treatment population, and oncolytic virus is administered at this time.

13. The method according to claim 1, wherein the method comprises 1) detecting the HLA typing of the patient and 2) detecting tumor antigens expressed by tumor cells.

14. The method according to claim 13, wherein the tumor is a solid tumor.

15. The method of claim 13, wherein the tumor includes soft tissue sarcoma, head and neck tumor, skin cancer, melanoma, liver cancer, gastric cancer, gynecological and / or genital tumors.

16. The method according to claim 13, wherein the tumor comprises synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, lymphoma, hepatocellular carcinoma, nasopharyngeal carcinoma, and / or gastric cancer.

17. The method according to claim 13, wherein the tumor antigen comprises MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg and / or EBV.

18. The method according to any one of claims 13-17, the method comprising detecting the following markers: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7; f) HLA typing is A02, and tumor antigen is HBsAg; and / or g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

19. The method according to any one of claims 13-17, the method comprising detecting the following markers: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7; f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

20. The method according to any one of claims 18-19, wherein when the biomarker described in any one of claims 18-19 is detected in a patient, the patient belongs to the oncolytic virus-preferred treatment population, and oncolytic virus is administered at this time.

21. The method according to any one of claims 1-20, further comprising detecting the integrity of the antigen presentation pathway.

22. The method of claim 21, wherein detecting the integrity of the antigen presentation pathway includes detecting whether an antigen presentation pathway protein is expressed, the antigen presentation pathway protein including antigen processing proteins and / or antigen transport proteins.

23. The method of claim 22, wherein the protein is selected from one or more of the group consisting of: TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and PSMB10.

24. The method according to claim 1, wherein the method comprises 1) detecting the HLA typing of a patient, 2) detecting tumor antigens expressed by tumor cells and 3) detecting the integrity of antigen presentation pathways.

25. The method of claim 24, wherein the method comprises detecting the following biomarkers in a patient, while simultaneously detecting whether proteins of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9 and / or PSMB10 are expressed in the antigen presentation pathway: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor The antigen is MART-1 and / or gp100; e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7; f) HLA typing is A02, and tumor antigen is HBsAg; and / or g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

26. The method of claim 24, wherein the method comprises detecting the following biomarkers in a patient, and simultaneously detecting whether proteins of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9 and / or PSMB10 are expressed in the antigen presentation pathway: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7; f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

27. The method according to any one of claims 25-26, wherein when the biomarker of any one of claims 25-26 is detected in a patient, the patient belongs to the oncolytic virus precision treatment population, and oncolytic virus is administered at this time.

28. A system for predicting oncolytic virus treatment populations, the system comprising a first module for detecting the patient's HLA typing.

29. The system according to claim 28, wherein the HLA typing is HLA-I type molecule.

30. The system according to claim 28, wherein the HLA typing is HLA-A02 typing.

31. The system of claim 28, wherein the HLA typing is selected from one or more of the following group: A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12 and DRB1.

32. The system according to any one of claims 28-31, when the HLA typing of any one of claims 27-30 is detected, predicts that the patient is a candidate for oncolytic virus treatment, and administers oncolytic virus at this time.

33. The system of claim 28, further comprising a second module for detecting tumor antigens expressed by tumor cells.

34. The system of claim 33, wherein the tumor is a solid tumor.

35. The system of claim 33, wherein the tumor includes soft tissue sarcoma, head and neck tumor, skin cancer, melanoma, liver cancer, gastric cancer, gynecological and / or genital tumors.

36. The system of claim 33, wherein the tumor comprises synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, hepatocellular carcinoma, and / or gastric cancer.

37. The system of claim 33, wherein the tumor antigen comprises MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg and / or EBV.

38. The system of claim 37, wherein when the tumor antigen of claim 37 is detected in a patient, the patient is predicted to be a candidate for oncolytic virus treatment, and oncolytic virus is administered at this time.

39. The system of claim 33, wherein the first module and the second module detect the following biomarkers in the patient: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7; f) HLA typing is A02, and tumor antigen is HBsAg; and / or g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

40. The system of claim 33, wherein the first module and the second module detect the following biomarkers in the patient: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7; f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

41. The system according to any one of claims 39-40, wherein when the biomarker of any one of claims 39-40 is detected in a patient, the patient is predicted to belong to the oncolytic virus-preferred treatment population, and oncolytic virus is administered at this time.

42. The system according to any one of claims 33-41, the system further comprising a third module for detecting the integrity of the antigen presentation pathway.

43. The system of claim 42, wherein detecting the integrity of the antigen presentation pathway includes detecting whether antigen processing proteins and / or antigen transport proteins are expressed.

44. The system of claim 43, wherein the protein is selected from one or more of the group consisting of: TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and PSMB10.

45. The system of claim 42, wherein the first and second modules detect the following biomarkers in the patient, while the third module detects whether proteins of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9 and / or PSMB10 are expressed in the antigen presentation pathway: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7; f) HLA typing is A02, and tumor antigen is HBsAg; and / or g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

46. ​​The system of claim 42, wherein the first and second modules detect the following biomarkers in the patient, while the third module detects whether proteins of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9 and / or PSMB10 are expressed in the antigen presentation pathway: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7; f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

47. The system according to any one of claims 45-46, wherein when the biomarker of any one of claims 45-46 is detected in a patient, the patient is predicted to be in the oncolytic virus precision treatment population, and the oncolytic virus is administered at this time.

48. An antitumor drug delivery platform, comprising an oncolytic virus drug module and a screening module for HLA typing in a patient population.

49. The platform according to claim 48, wherein the HLA typing is HLA-I type molecule.

50. The platform according to claim 48, wherein the HLA typing is HLA-A02 typing.

51. The platform according to claim 48, wherein the HLA typing is selected from one or more of the following group: A01, A02, A03, A11, A24, A31, A32, A68, B07, B35, B45, B51, B52, C12 and DRB1.

52. In the platform according to any one of claims 48-51, when the HLA typing described in any one of claims 48-51 is found to have a distribution frequency of more than 40% in the patient population, the population belongs to the oncolytic virus treatment population, and oncolytic virus is administered at this time.

53. The platform according to claim 48, wherein the screening module further includes screening for tumor antigens expressed by tumor cells.

54. The platform according to claim 53, wherein the tumor is a solid tumor.

55. The platform according to claim 53, wherein the tumor includes soft tissue sarcoma, head and neck tumor, skin cancer, melanoma, liver cancer, gastric cancer, gynecological and / or genital tumors.

56. The platform according to claim 53, wherein the tumor includes synovial sarcoma, myxosarcoma, liposarcoma, adenoid cystic carcinoma, thymic carcinoma, oropharyngeal carcinoma, head and neck squamous cell carcinoma, skin cancer, malignant melanoma, cervical cancer, vulvar cancer, vaginal cancer, penile cancer, hepatocellular carcinoma, and / or gastric cancer.

57. The platform according to claim 53, wherein the tumor antigens include MAGE-A4, PRAME, NY-ESO-1, HPV E6 / E7, MART-1, gp100, HBsAg and / or EBV.

58. According to the platform of claim 57, when the tumor antigen expression frequency is found to be above 40%, the population belongs to the oncolytic virus treatment population, and oncolytic virus is administered at this time.

59. The platform according to claim 53, screening for the following biomarkers in the patient population: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7; f) HLA typing is A02, and tumor antigen is HBsAg; and / or g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

60. The platform according to claim 53, screening for the following biomarkers in the patient population: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7; f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

61. In the platform according to any one of claims 59-60, when the biomarker according to any one of claims 59-60 appears more than 40% in the patient population, the patient population belongs to the oncolytic virus dominant treatment population, and oncolytic virus is administered at this time.

62. The platform according to any one of claims 48-61, wherein the screening module further includes screening for whether an antigen presentation pathway protein is expressed.

63. The platform according to claim 62, wherein the antigen presentation pathway proteins include antigen processing proteins and / or antigen transport proteins.

64. The platform according to claim 63, wherein the protein is selected from one or more of the group consisting of: TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9, and PSMB10.

65. The platform according to claim 62, screening for the following biomarkers in a patient population, while simultaneously screening for the expression of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9 and / or PSMB10 proteins in the antigen presentation pathway: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01, A02, A03, A11 and / or A24, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor The antigen is MART-1 and / or gp100; e) HLA typing is A02, A11 and / or DRB1, and tumor antigen is HPV E6 / E7; f) HLA typing is A02, and tumor antigen is HBsAg; and / or g) HLA typing is A02, A11 and / or A31, and the tumor antigen is EBV.

66. The platform according to claim 62, screening for the following biomarkers in a patient population, while simultaneously screening for the expression of TAP1, TAP2, TAPBPL, ERAP1, ERAP2, PSMB8, PSMB9 and / or PSMB10 proteins in the antigen presentation pathway: a) HLA typing is A01, A02 and / or A24, and tumor antigen is MAGE-A4; b) HLA typing of A02, A11, A24, A31, A68, B07, B35, B51, B52 and / or C12, and tumor antigen of NY-ESO-1; c) The HLA type is A01:01, A02:01, A03:01, A11:01 and / or A24:02, and the tumor antigen is PRAME; d) HLA typing of A02, A03, A11, A24, A32, A68, B07, B35 and / or B45, and tumor antigen of MART-1 and / or gp100; e) HLA typing is A02:01, A11:01 and / or DRB1 09:01, and tumor antigen is HPV E6 / E7; f) HLA typing of A02:01, A02:03 and / or A02:07, and tumor antigen of HBsAg; and / or g) HLA typing is A02, A11:01 and / or A31:01, and tumor antigen is EBV.

67. According to any one of claims 65-66, when the biomarker described in any one of claims 65-66 is found to be expressed at a frequency of 40% or higher in the patient population, the patient population belongs to the oncolytic virus precision treatment population, and oncolytic virus is administered at this time.

68. A detection kit comprising a first reagent for detecting HLA typing, a second reagent for detecting tumor antigen expression, and / or a third reagent for detecting the integrity of an antigen presentation pathway, wherein the HLA typing is an HLA class I molecule, the tumor antigen is a tumor antigen of a solid tumor, and the detection of the integrity of the antigen presentation pathway is the detection of whether an antigen presentation pathway protein is expressed.

69. Use of biomarkers in the preparation of oncolytic virus prediction systems and / or antitumor drug screening platforms, wherein the biomarkers include HLA typing, tumor antigens and / or antigen presentation pathway proteins, wherein the HLA typing is an HLA-I molecule, the tumor antigen is a tumor antigen of a solid tumor, and the detection of antigen presentation pathway integrity is the detection of whether antigen presentation pathway proteins are expressed.

70. HLA typing, antigen-presenting pathway proteins and / or tumor antigens, used to screen patients for oncolytic virus therapy, wherein the HLA typing is HLA-I molecules, the tumor antigen is a tumor antigen of solid tumors, and the detection of antigen-presenting pathway integrity is to detect whether antigen-presenting pathway proteins are expressed.

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