Application of oncolytic virus combined PD-1 monoclonal antibody in preparation of melanoma treatment medicine

Abstract

The invention is applicable to the technical field of medicines for treating melanoma, and provides application of oncolytic viruses combined with PD-1 monoclonal antibodies in preparation of medicines for treating melanoma. The invention further provides a melanoma treatment medicine. The medicine comprises the oncolytic virus and the PD-1 monoclonal antibody. According to the invention, the oncolytic virus and the PD-1 monoclonal antibody are combined for use, due to the oncolytic characteristic of the herpes simplex virus, the modified HSV-1 virus vector performs specific oncolytic treatment at an injection site to kill tumor cells, and the virus vector is expressed at the tumor site to generate high-concentration GM-CSF to enhance the anti-tumor immune function of a body and exert a side-killing effect; the inhibition effect is generated on the metastatic tumor at the far end; the PD-1 monoclonal antibody can be combined with PD-1 on the surface of a T cell to block the combination of the PD-1 monoclonal antibody and ligands PD-L1 and PD-L2, so that the immunosuppression of tumor cells on a PD-1 signal channel is eliminated, the proliferation of the T cell can be promoted, the function of the T cell can be activated, the tumor growth can be inhibited, and the combination of the PD-1 monoclonal antibody and the PD-1 monoclonal antibody can improve the immune microenvironment of the melanoma and improve the treatment efficiency; the invention shows excellent curative effect and good prospect in the field of neoadjuvant therapy of high-risk melanoma.

Description

Technical Field

[0001] The present invention belongs to the technical field of melanoma therapeutic drugs, and in particular relates to the use of oncolytic viruses combined with PD-1 monoclonal antibodies in the preparation of melanoma therapeutic drugs. Background Art

[0002] Acral melanoma (AM) is a highly aggressive subtype of melanoma with a high incidence in the Chinese population, accounting for approximately 40% of melanoma cases. Despite significant progress in the treatment of melanoma, AM patients have limited benefit from common immunotherapies such as PD-1 monoclonal antibodies and lack effective adjuvant treatment options. Compared with stage III-IV cutaneous melanoma, AM patients have a significantly reduced recurrence-free survival (RFS) (14.8 months vs 37.4 months, p = 0.002), and patients with stage IIIB-IVM1a melanoma still have a high risk of recurrence after complete resection. In theory, neoadjuvant immunotherapy can induce a stronger immune response than adjuvant therapy because the presence of tumor antigens is more obvious compared with adjuvant therapy strategies. Neoadjuvant interventions significantly improve the treatment effect of patients compared with adjuvant therapy after surgery. Compared with adjuvant therapy, neoadjuvant therapy is more effective for patients with stage III melanoma, which may have a significant impact on future melanoma treatment options. However, despite the remarkable efficacy of neoadjuvant immunotherapy in cutaneous melanoma, the search for effective neoadjuvant regimens for AM continues. Given the limited efficacy of anti-PD-1 monotherapy in AM, combination therapy is a promising approach.

[0003] Oncolytic virus therapy is an effective immunotherapy option. The typical representative of local oncolytic virus immunotherapy is talimogene laherparepvec (T-VEC), which has been approved for the treatment of unresectable stage IIIB-IVM1a melanoma with lymph node, subcutaneous or skin metastases. T-VEC can reshape the tumor microenvironment and transform immune-deficient "cold" tumors into immunogenic "hot" tumors, thereby increasing their sensitivity to immune checkpoint inhibitor (ICI) treatment. Summary of the invention

[0004] The purpose of the embodiments of the present invention is to provide an application of oncolytic virus combined with PD-1 monoclonal antibody in the preparation of melanoma therapeutic drugs, aiming to solve the problems raised in the above background technology.

[0005] The embodiment of the present invention is achieved by using an oncolytic virus in combination with PD-1 monoclonal antibody in the preparation of a drug for treating melanoma.

[0006] Preferably, the oncolytic virus uses human herpes virus type 1 HSV-1 as a vector, and uses gene recombination technology to successively delete ICP34.5, ICP47, and insert inactivated ICP6 genes, and insert the human GM-CSF gene guided by the hCMV IE promoter at the original ICP34.5 site.

[0007] Another object of an embodiment of the present invention is to provide a melanoma treatment drug, which includes an oncolytic virus and a PD-1 monoclonal antibody.

[0008] Preferably, the drug is an injectable preparation.

[0009] The oncolytic virus provided in the embodiment of the present invention is combined with PD-1 monoclonal antibody for the preparation of a melanoma therapeutic drug. The oncolytic virus and PD-1 monoclonal antibody are used in combination, wherein the oncolytic virus is isolated from the oral cavity of a Chinese patient using type I herpes simplex virus HSV-1 as a vector, and ICP34.5, ICP47 and inactivated ICP6 genes are deleted successively by gene recombination technology, and the human GM-CSF gene guided by the IE promoter of hCMV is inserted into the original ICP34.5 site. Its anti-tumor mechanism is similar to that of T-Vec. After local injection of the gene into the tumor site, it can exert an anti-tumor effect through two mechanisms: on the one hand, due to the oncolytic properties of the herpes simplex virus, the modified HSV-1 virus vector specifically "dissolves" and kills tumor cells at the injection site; on the other hand, the virus vector expresses a high concentration of GM-CSF at the tumor site to enhance the body's anti-tumor immune function, exert a "bystander effect", and inhibit distant metastatic tumors, specifically:

[0010] HSV-1 with ICP34.5 deleted cannot replicate in normal cells or tissues due to the shutdown of protein synthesis, but it still retains the ability to replicate in malignant tumor cells, thus having a selective oncolytic effect;

[0011] Deleting ICP47 makes tumor cells infected by the vector more easily recognized by the immune system, thereby enhancing the presentation of tumor antigens released by the oncolytic vector after destroying tumor cells to the body's immune system, amplifying the anti-tumor immune response, and at the same time enhancing the replication ability of the viral vector in tumor cells and improving the oncolytic ability of the vector;

[0012] Inserting the inactivated ICP6 gene can further enhance the high selectivity and specificity of OrienX010 for tumor cells, thereby increasing safety. The HSV-1 vector with the inactivated ICP6 gene also exhibits reduced neurotoxicity and is highly sensitive to the antiviral drugs acyclovir and ganciclovir.

[0013] The mechanism of action of PD-1 monoclonal antibody is as follows: the PD-1 receptor expressed by T cells binds to its ligands PD-L1 and PD-L2, which can inhibit T cell proliferation and cytokine production. The PD-1 ligands of some tumor cells are upregulated, which can inhibit the immune surveillance of tumors by activated T cells. PD-1 monoclonal antibody can bind to PD-1 on the surface of T cells, blocking its binding with ligands PD-L1 and PD-L2, thereby eliminating the immunosuppression of tumor cells on the PD-1 signaling pathway, promoting T cell proliferation, activating T cell function, and inhibiting tumor growth. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 A line graph showing changes in tumor volume under treatment with oncolytic virus combined with PD-1 monoclonal antibody compared with oncolytic virus alone and PD-1 monoclonal antibody alone provided in Example 2 of the present invention (vehicle: blank control);

[0015] Figure 2 This is a bar graph showing the change in tumor volume on the 12th day under the treatment of oncolytic virus combined with PD-1 monoclonal antibody provided in Example 2 of the present invention, compared with oncolytic virus alone and PD-1 monoclonal antibody alone (vehicle: blank control). DETAILED DESCRIPTION

[0016] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0017] Immune checkpoint inhibitors (such as PD-1 inhibitors) are one of the main treatments for melanoma, but the effectiveness of immune checkpoint inhibitors in treating the main subtype of melanoma in China: acral melanoma is very worrying. Related studies have shown that the effectiveness of anti-PD-1 monotherapy is 23%, which is only half of that of cutaneous melanoma (CSD and NCSD), and the PFS time is significantly lower than that of patients with cutaneous melanoma. The above studies suggest that finding effective combined treatment strategies to improve the therapeutic effect of PD-1 monoclonal antibodies is particularly important for solving the treatment problems of melanoma patients in China.

[0018] Patients who respond to immune checkpoint inhibitors have a certain degree of anti-tumor immunity before treatment, and there is cytotoxic T cell infiltration in the patient's tumor tissue; 80-90% of patients do not respond to this type of immune checkpoint inhibitor treatment due to lack of anti-tumor immunity and immunosuppression in the tumor microenvironment (TME). Pre-existing tumor-killing T cells in the tumor microenvironment (TME) are the key to the clinical treatment response of immune checkpoint inhibitors.

[0019] Basic research has found that the function, density and distribution of immune cells inside tumors are significantly correlated with the survival of tumor patients. According to the characteristics of "immune structure", tumors can be divided into several immune types: hot, variable and cold tumors; cold tumors are characterized by the absence of T cells inside and at the edge of the tumor, and low T cell activity (low tumor mutation load and poor antigen expression). Domestic and foreign literature reports in recent years suggest that acral melanoma has a unique genetic background and biological characteristics. The genomic variations of skin melanoma are mainly point mutations, insertions, and deletions; the genomic characteristics of the acral subtype are more manifested as structural variations of genes and low tumor mutation load. Compared with skin melanoma with a high tumor mutation load rate, acral melanoma has low immunogenicity and a high proportion of cold tumors, which may be one of the important reasons why this subtype is not effective for PD-1 monoclonal antibodies.

[0020] Oncolytic viruses (OVs) infect tumor cells and can effectively promote T cell infiltration, which paves the way for immune checkpoint inhibitors to achieve maximum efficacy. OVs mainly work in the following aspects: (1) OVs selectively replicate in tumor cells, with good specificity and few side effects; OVs lyse tumor cells in situ, release tumor-associated antigens and cytokines, and promote antigen-presenting cells to recruit tumor-killing T cells. Reports show that tumor cells infected with oncolytic herpes simplex virus (oHSV) can promote the maturation of DC cells and the expression of MHC class II molecules; (2) OVs can promote the infiltration of T cells in the tumor. Viral infection can stimulate the production of T cell recruitment chemokines; OVs can induce inflammatory responses, upregulate the expression of selectins on endothelial cells, and provide key signals for T cell infiltration; (3) OVs can rebuild and improve the immune status of the tumor microenvironment and increase the number of tumor-killing T cells in the tumor microenvironment. The tumor microenvironment (TME) in solid tumors is highly immunosuppressive, affecting the efficiency of tumor-specific T cell infiltration, limiting innate and adaptive antitumor immunity and promoting tumor growth. Antitumor T cells, whether endogenously induced or exogenously transferred, are in a damaged state of exhaustion in the immunosuppressive microenvironment. The recognition of viruses by the body's innate defense mechanism is not affected by the tumor immunosuppressive microenvironment; OVs can counteract immunosuppression in the tumor microenvironment by inducing an effective pro-inflammatory T helper cell 1 (TH1) polarized immune response. PD1 / PDL1 immune checkpoint inhibitors tend to work in "hot tumors (CD8+ infiltration, neoantigens and PDL1 expression)". For immunosuppressive "cold tumors", the efficacy of immune checkpoint inhibitors is often unsatisfactory. In tumors with poor immunogenicity, there are almost no tumor-infiltrating lymphocytes, the tumor microenvironment lacks type I interferon signals and T cell recruitment chemokines, and the vascular and matrix components in the tumor may also hinder the intratumoral infiltration of T cells and their effectors. Oncolytic viruses can transform the tumor microenvironment from an immunosuppressive state (cold tumor) to an inflammatory state (hot tumor). (4) Oncolytic viruses can induce systemic anti-tumor immune responses. Oncolytic viruses have immune activation effects on a variety of immune cells, including DC cells, T cells, NK cells, etc. Local administration of oncolytic viruses can induce systemic anti-tumor immune responses, leading to the regression of tumors at distal non-injection sites, while avoiding the toxicity of systemic administration.

[0021] Oncolytic virus therapy can improve the immune microenvironment of tumors and transform cold tumors. Tumor cell death induced by oncolytic virus infection is an immunogenic cell death, which is exposed through the secretion, release and exposure of danger-related molecules, cytokines and tumor antigens, promotes the maturation of antigen-presenting cells, leads to the activation of antigen-specific CD4+ and CD8+T cells, and induces anti-tumor immune response.

[0022] The PD-1 monoclonal antibody used in the embodiment of the present invention is Toripalimab injection (trade name: Tori). On December 17, 2018, the National Medical Products Administration conditionally approved the first domestically produced PD-1 monoclonal antibody for the treatment of locally advanced or metastatic melanoma after failure of previous standard treatment. The molecular formula of Toripalimab is C 6548 H 10104 N 1728 O 2054 S 44 , is a monoclonal antibody designed to target the PD-1 receptor on immune cells. The combination of Teplizumab and PD-1 can prevent cancer cells from escaping the immune system, help overcome the immunosuppression in the patient's body, and reactivate the body's own immune cells to help identify and kill tumor cells, thereby achieving the effect of controlling the disease.

[0023] The specific implementation of the present invention is described in detail below in conjunction with specific embodiments.

[0024] Example 1. Application of oncolytic virus combined with PD-1 monoclonal antibody in the preparation of melanoma treatment drugs, wherein the oncolytic virus used is a genetically modified oncolytic virus derived from human herpes virus type 1 (HSV), named OrienX010, and its specific genetic modification process is a prior art, see the patent application with publication number CN116209751A for details.

[0025] Example 2: Comparison of the tumor inhibition effects of oncolytic virus combined with PD-1 monoclonal antibody versus oncolytic virus alone and PD-1 monoclonal antibody alone:

[0026] B16 mouse melanoma cell line was inoculated subcutaneously in mice. When the tumor volume reached about 70 mm 3 The mice were then randomly divided into groups and treated with OrienX010 (oncolytic virus) combined with PD-1 monoclonal antibody, PD-1 monoclonal antibody alone, or OrienX010 alone for 12 consecutive days. The results are as follows: Figure 1 , Figure 2 As shown, according to Figure 1 , Figure 2 It can be seen that the results show that the tumor inhibition effect of oncolytic virus combined with PD-1 monoclonal antibody is better than that of OrienX010 alone and PD-1 monoclonal antibody alone. The change data are shown in Table 1:

[0027] Table 1 Changes in tumor volume under oncolytic virus combined with PD-1 monoclonal antibody treatment vs. oncolytic virus alone and PD-1 monoclonal antibody alone

[0028]

[0029]

[0030] Note: N1-7: B16 mouse numbers; %: percentage of tumor size increase

[0031] Example 3: Open Phase Ib Clinical Analysis of Oncolytic Virus Combined with PD-1 Monoclonal Antibody Neoadjuvant Therapy for Completely Resectable Stage III and IV (M1a) Melanoma:

[0032] Materials and methods: This study was a single-arm, open-label, single-center phase Ib clinical trial conducted in the Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, China (clinical trial number: NCT04197882), which was approved by the Ethics Committee of Peking University Cancer Hospital and Institute (approval number: 2019YJZ35). It was used to evaluate the efficacy and safety of the combined use of ori (oncolytic virus OrienX010) and tori (PD-1 monoclonal antibody) as neoadjuvant treatment for patients with acral melanoma. The primary endpoint was the radiological and pathological response rate according to the RECIST 1.1 standard. Secondary endpoints included 1-year and 2-year recurrence-free survival (RFS, the time from surgery to recurrence for surgical patients), event-free survival (EFS, the time from the start of treatment to recurrence, applicable to all patients), overall survival (OS, the time from randomization to death from any cause) and safety.

[0033] Patients: Eligible patients were aged between 18 and 75 years and had to be histologically and / or cytologically confirmed to have resectable stage III and IVM1a AM that met the eighth edition staging criteria of the AJCC (American Joint Committee on Cancer). In addition, patients were required to have at least one measurable lesion that met the RECIST 1.1 criteria and was suitable for intralesional injection therapy, including injectable lymph node, subcutaneous or skin melanoma lesions (longest diameter ≥10mm); the patient's Eastern Cooperative Oncology Group (ECOG) performance status was required to be ≤1 and have good organ function. All enrolled patients signed written informed consent.

[0034] The test process is divided into three stages:

[0035] Neoadjuvant treatment stage: Ori combined with tori injection, the Tori injection dose is 3 mg / kg, intravenous infusion once every two weeks, for a total of six times; the maximum dose of Ori is 8×10^8 pfu, up to 10 mL, intratumoral injection, once every two weeks, for a total of six times;

[0036] Surgical treatment phase: Surgery was performed 2 weeks (±7 days) after the last neoadjuvant treatment;

[0037] Adjuvant therapy phase: 3 weeks (±7 days) after surgery, patients were given tori injections. The Tori injection dose was 3 mg / kg, and it was intravenously infused once every 3 weeks. The treatment duration was up to 1 year (1 year was calculated from the first dose of neoadjuvant therapy).

[0038] Evaluation: Tumor imaging examinations (CT / MRI and PET / CT) were performed at the screening period and at the 12th week of neoadjuvant treatment to evaluate the anti-tumor effect. During postoperative adjuvant treatment, patients were followed up with tumor imaging every 3 months, every 4 months in the second year, and every 6 months from the third to the fifth year.

[0039] The criteria for pathological response were based on the International Neoadjuvant Melanoma Consortium scoring system: partial pathological response (pPR, 10% ≤ active tumor cells ≤ 50%); near complete pathological response (Near pCR, 0% <

[0040] Active tumor cells <10%); complete pathological response (pCR, no active tumor cells), pathological response includes pPR, Near pCR and pCR, no pathological response (pNR, active tumor cells>50%);

[0041] Methods: Cytokines and chemokines were measured in 32 serum samples from 16 patients at baseline and 6 weeks after neoadjuvant treatment (C3) using proximity extension assays developed by Olink Proteomics (Sweden). Analysis was performed by Panovue (Beijing, China). Olink's standard protocols were used for quality control and data normalization, with internal and external control references and completed in the Olink Normalized Protein Expression (NPX) Manager Software (V.3.3.2.434).

[0042] result:

[0043] Patient characteristics:

[0044] Between July 2019 and December 2020, 43 candidates signed informed consent, 33 eligible patients were included in the trial, 30 patients received study treatment, and 3 patients withdrew. The main reason for screening failure was distant metastasis. Among the 30 patients who received study treatment, the median age was 57 years (range 21–72 years), 47% were male, and the stage distribution was 40% for stage IIIB, 47% for stage IIIC, and 13% for stage IVM1a. Only 20% of patients had BRAF mutant melanoma. The median diameter of the target lesion was 28 mm;

[0045] In neoadjuvant therapy, an average of 5.6 ori and tori doses (4-6 times) were given, with an average ori dose of 8.9 mL (3-10 mL). Three patients did not undergo surgery due to distant metastases during neoadjuvant therapy (three patients with primary metastases in the foot, two visceral metastases, and one lymph node metastasis). Of the remaining 27 patients who underwent surgery, all subsequently received adjuvant therapy. However, two patients chose to stop adjuvant therapy due to toxic reactions.

[0046] Clinical efficacy:

[0047] Radiographic response:

[0048] According to the solid tumor response evaluation criteria (RECIST 1.1) and pathological response criteria, the radiographic response rate of 30 patients who received study treatment was 36.6% (1 complete remission CR and 10 partial remission PR); 40% had stable disease SD, and 23.4% had progressive disease PD. The pathological response and radiographic response were inconsistent. For example, among the 12 patients who achieved major pathological response (pCR + close to pCR), only 3 had radiographic partial remission PR.

[0049] Pathological reaction:

[0050] According to the pathological response definition in the methodology, 27 (90%) of the 30 patients who received treatment underwent surgery; 4 (14.8%) of them achieved complete pathological response (pCR), 5 (18.5%) were close to pCR, 12 (44.5%) were partial pathological response (pPR), 6 (22.2%) had no pathological response, 33.3% of the patients achieved major pathological response, and 77.8% of the patients achieved pathological response (pCR+close to pCR+pPR). Among the 5 patients who underwent surgery on lymph nodes and primary lesions, the pathological response was different. Among them, 4 patients achieved pCR in the primary lesion, but only 1 patient had a lymph node lesion close to pCR.

[0051] Responses were observed in both injected and non-injected lesions, with 25 (62.5%) of 48 measurable lesions (40) receiving ori-directed injections showing radiographic regression. Of the eight non-injectable lesions (all regional), five patients (62.5%) showed radiographic responses, and five of six patients (83.3%) showed pathological responses.

[0052] Recurrence-free survival (RFS):

[0053] As of April 30, 2023, the median follow-up was 35.7 months (range 12.0–49.1 months), and the 1-year and 2-year RFS rates were 85.2% and 81.5%, respectively. The median RFS has not yet been reached, and the average RFS is 40.3 months. At the last follow-up, 5 patients had relapses, including 3 lymph node metastases, 1 lung metastasis, and 1 intestinal metastasis. Among the relapsed patients, 3 had no pathological response (all lymph node metastases), 1 had partial pathological remission (pPR), and 1 had major remission / close to pCR;

[0054] In patients with pathological response, the median RFS had not yet been reached (mean, 43.5 months), which was significantly longer than the 28.8 months (median, 14.2 months) in patients with pathological non-response (pNR) (p = 0.016). In addition, there was no significant difference between the pCR + near pCR group and the pPR group (mean, 40.5 months vs. 46.4 months).

[0055] Event-free survival (EFS):

[0056] The 1-year and 2-year EFS rates were 83% and 73%, respectively. The median EFS has been reached, with an average EFS of 35.7 months. Subgroup analysis showed that patients with normal baseline LDH levels had significantly longer median EFS than those with high baseline LDH levels, not reached vs. 12.75 months (CI: 4.947–20.553, p=0.001). There were no significant differences between patients of different ages, genders, stages, gene mutations, and ECOG scores.

[0057] Overall survival (OS):

[0058] As of the last follow-up, 4 patients died of tumor progression, 3 of whom were unable to undergo surgery after neoadjuvant therapy due to distant metastasis. The 12-month and 24-month OS were 96% and 90%, respectively, and the average OS was 45.3 months (median not reached). The OS of patients with pathological response was improved (median not reached; 1-year and 2-year OS were 100%). In contrast, the 1-year and 2-year OS of patients with pathological non-response (pNR) was 83.3% (p = 0.061), but the difference was not statistically significant. In addition, there was no significant difference between the pCR + near pCR group and the pPR group. Subgroup analysis showed that the median OS of patients with normal baseline LDH levels was significantly prolonged (not reached vs. 37.5 months; CI: 22.158–52.699, p = 0.005). There were no significant differences in age, gender, stage, gene mutation, and ECOG score;

[0059] Toxic reactions:

[0060] The combination was well tolerated, with all patients experiencing treatment-related adverse events (TRAEs), most of which were grade 1 or 2 (25 / 30, 83.3%), and 4 patients (13.3%) reported grade 3 adverse events (2 soft tissue infections, 1 aspartate aminotransferase [AST] increase, and 1 peripheral neuropathy). Of all adverse events, 93.3% were attributed to the combination therapy, while 13.3% were related to the use of ori alone. Only 2 grade 3 treatment-related adverse events were observed (1 AST increase and 1 peripheral neuropathy), both of which occurred during the adjuvant treatment phase;

[0061] Cytokine and chemokine analysis:

[0062] Olink technology was used to quantitatively analyze circulating inflammatory proteins (liquid biopsy). A total of 32 serum samples from 16 patients (8 pCR+ close to pCR and 8 pNR patients) were collected and analyzed before treatment (baseline) and after treatment (6 weeks: C3). The analysis results showed that the combination of oncolytic virus and anti-PD-1 monoclonal antibody significantly increased the secretion of cytokines and chemokines (including IFN-γ, GZMA, CXCL10 and IL12) in both groups of patients, suggesting that this combination can enhance immune activity and improve the efficacy of immunotherapy.

[0063] In summary, the open-label Phase Ib clinical study of recombinant human GM-CSF herpes simplex virus injection (OrienX010) combined with recombinant humanized anti-PD-1 monoclonal antibody injection (toripalimab injection) in the neoadjuvant treatment of completely resectable stage III and IV (M1a) melanoma aims to clarify the efficacy of oncolytic virus combined with PD-1 inhibitor drugs in the neoadjuvant treatment of acral melanoma and explore its mechanism of action. Good data such as pathological response rate and progression-free survival rate were obtained, and cytokine-related studies confirmed that this combination regimen can activate the immune microenvironment of acral melanoma.

[0064] The 1-year and 2-year RFS rates of this combination regimen were 85.2% and 81.5%, respectively. For patients with pathological remission, the median recurrence-free survival (RFS) has not yet been reached, but can be as long as 43.5 months on average, which is significantly better than the data of adjuvant therapy.

[0065] The application of PD-1 monoclonal antibody in the neoadjuvant treatment of melanoma can better reduce the risk of recurrence and metastasis of locally advanced melanoma and improve the prognosis, thereby indirectly achieving the purpose of reducing the melanoma metastasis rate, improving the overall melanoma prognosis, and reducing treatment costs.

[0066] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. Application of oncolytic virus combined with PD-1 monoclonal antibody in the preparation of melanoma therapeutic drugs.

2. The use of an oncolytic virus combined with PD-1 monoclonal antibody in the preparation of a drug for treating melanoma according to claim 1, characterized in that: The oncolytic virus uses human herpes virus type 1 HSV-1 as a vector, and uses gene recombination technology to delete ICP34.5, ICP47 and insert inactivated ICP6 genes, and insert the human GM-CSF gene guided by the IE promoter of hCMV at the original ICP34.5 site.

3. A drug for treating melanoma, characterized in that: The drug comprises the oncolytic virus as described in claim 1 or 2 and PD-1 monoclonal antibody.

4. The melanoma therapeutic drug according to claim 3, characterized in that: The medicine is an injection preparation.

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