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Immunotherapy: Combination therapy of CAR-T cells and oncolytic virus

Immunotherapy: Combination therapy of CAR-T cells and oncolytic virus. A new era of tumor immunotherapy!

CAR-T cell therapy is used to treat various types of tumors in the human body. It has been successful in hematological malignancies, but has poor efficacy in solid tumors.

Oncolytic viruses (Oncoltic Viurs, OV) can selectively replicate in tumors, and can deliver immune and therapeutic genes to breakthrough tumor environments through genetic engineering to enhance the cytotoxic activity of CAR-T cells. -T cells produce a synergistic effect.

Recently, Ramazan Rezaei et al. published a review on Cancer Gene Therapy, a sub-Journal of Natrue, and conducted a comprehensive review of the combined use of CAR-T cell therapy and oncolytic virus therapy in the treatment of solid tumors, and launched a review on its challenges and future prospects. discuss.

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01.  Oncolytic virus therapy

T-Vec is a genetically modified herpes simplex virus type 1 (HSV-1) and is the first OVs-based drug approved in the United States and Europe. It can replicate and express the immune activation protein granulocyte-macrophage colony stimulating factor (GM-CSF) in tumor cells, enhance the body’s anti-tumor immune response, and is mainly used for the treatment of advanced melanoma tumors.

The similar oncolytic virus G47∆ is a new generation of HSV-1 oncolytic virus product based on the HSV-1 virus knocking out ICP34.5 and deleting ICP47. The oncolytic virus treatment of recurrent glioblastoma is in the second phase of clinical trials. (Supplement: G47∆ is jointly developed by Daiichi Sankyo Co., Ltd. and the Institute of Medical Science, University of Tokyo, Japan. It was approved by the Ministry of Health, Labour and Welfare (MHLW) on June 11, 2021 for the treatment of malignant glioma , Is the second oncolytic herpes simplex virus product and the world’s first oncolytic virus product approved for the treatment of malignant glioma.)

Currently, oncolytic adenovirus CG0070 is used to treat non-muscular invasive bladder cancer, vaccinia virus JX-594 is used to treat colorectal cancer and hepatocellular carcinoma, and reo oncolytic virus (REO) is used for metastatic melanoma and pancreatic cancer. All have entered clinical phase III.

In addition, dozens of clinical trials of oncolytic virus products alone or in combination are underway globally.

As we all know, whether oncolytic viruses replicate specifically in tumors and whether they can induce the body to produce specific anti-tumor immunity are two key factors to ensure the success of OVs treatment.

Genetically modified oncolytic viruses have made breakthrough progress in the field of tumor therapy, and researchers need to continue to pay attention to the safety, therapeutic effect and reduction of side effects of oncolytic virus therapy.

02. CAR-T cell therapy in solid tumors

CAR-T cell immunotherapy uses targeted modification of T cells to identify tumor cells and thereby target them to be killed. CAR-T cells have achieved good therapeutic effects in the treatment of hematoma, but their application in solid tumors has been challenged.

For example: CAR-T cells are immunosuppressed in the tumor microenvironment (TME), CAR-T cells have limited transport capacity, heterogeneity, lack of ideal specific target tumor antigens, reduced in vivo proliferation efficiency, and survival time in vivo Limited wait. The treatment of solid tumors by CAR-T cells requires technological breakthroughs or other treatment methods.

03.  Cold tumors transformed into hot tumors

01) OVs mediate local inflammation

Studies have shown that one of the mechanisms by which OVs induce anti-tumor activity is to activate the body’s anti-tumor immunity by inducing the production of type I interferons (IFNs) and other inflammatory stimulants in TME.

The effector T cells are generally activated through three signal pathways: 1) the signal transmitted when the T cell receptor (TCR) interacts with the antigen; 2) through the coordination of immunostimulatory molecules and their expression on antigen presenting cells (APC). Signals mediated by body binding; 3) Stimulus signals produced by pro-inflammatory cytokines or mediators.

After T cells are transformed into CAR-T cells, they already have the stimulation of the first two signal pathways. After OVs infect tumor cells, the pro-inflammatory cytokines produced in TEM can generate the third signal stimulus mentioned above, which can activate and enhance the killing effect of CAR-T cells on tumor cells, turning Cold Tumor into Hot Tumor.

02) Immunogenic cell death induced by OVs

OVs infect cells to release internal damage-related molecules (DAMP), such as: hsp70 & hsp90), HMGB1, IL-1a, IL-33, ATP, mRNA, etc., causing immunogenic cell death (ICD) through dendritic cells (DC) activation to induce anti-tumor immune response.

OVs also induce ER stress in tumor cells, thereby increasing the level of intracellular reactive oxygen species (ROS), increasing protein kinase R-like endoplasmic reticulum kinase (PERK) and promoting mitochondrial apoptosis to achieve cell killing.

In addition, the production of type I IFN by OVs can also increase the infection of new tumor cells by OVs, or stimulate the expression of MHC-1 in uninfected tumor cells, thereby enhancing the body’s anti-tumor cell immunity.

03) Reverse TME immunosuppressive signal

In the tumor microenvironment (TME), fibroblasts and stromal cells related to tumor cells inhibit the body’s anti-tumor immunity by producing and recruiting immunosuppressive molecules or cells, resulting in an immunosuppressive tumor microenvironment.

After OVs infect tumor cells, it will trigger the production of pro-inflammatory cytokines, PAMPs and DAMPs, induce a large number of immune cells to infiltrate TEM, and then by uptake OVs to lyse tumor cells produced by tumor-associated antigens (TAA), mature DCs will Presented to cytotoxic T cells. Subsequently, the activated CD8+ T cells produce perforin and granzyme to kill specific tumor cells.

OVs also target tumor stromal cells such as fibroblasts (CAF) and endothelial cells to destroy the tissue structure of TME, increase permeability, and guide more immune cell infiltration. It counteracts the immunosuppressive properties of TME and promotes the therapeutic effect of CAR-T cells.

04) Inhibit tumor recurrence

Even if cancer patients receive initial benefits after surgery, chemotherapy, and radiotherapy, later recurrence is still the main risk and clinical challenge. The main reasons for its recurrence include: tumor stem-like cells, immune escape tiny lesions or tumor cells.

It has been reported that oncolytic adenovirus can effectively destroy cancer stem cells (CSC) and cause cell death through a variety of mechanisms. For example, the oncolytic adenovirus DNX-2401 can significantly extend the survival period of patients with recurrent malignant glioma. The number of CD8 positive T cells and T-bet positive cells in TME increased significantly, and the expression of TIM-3 gene was down-regulated.

For patients treated with CAR-T cell therapy, tumor cells can achieve immune escape through a variety of mechanisms and lead to later recurrence, such as: loss or down-regulation of target antigens, antigen mutations, selective survival of antigen-negative cancer cells to escape immunity, etc. .

OVs can target tumor cells and prevent antigen-negative recurrence by stimulating endogenous immune effector cells (CD+ T cells, etc.) and CAR-T cells.

04.  Improve OVs to enhance the function of CART

Based on the viral genome modification technology, some genes with anti-tumor effects are constructed into the viral genome. When OVs infect tumor cells, the expression profile of cytokines or chemokines in TME will change, which promotes the infiltration and proliferation of CAR-T cells. And lasting.

01) Delivery through cytokines

In recent years, cytokines have been increasingly identified as important therapeutic agents for the treatment of patients with advanced cancer or metastatic cancer. OVs carrying cytokines locally is a more suitable and safer strategy for use with CAR-T cell therapy. So far, OVs armed with various cytokines have been designed, such as: TNF-α, GM-CSF and IL -12 Isogenic insertion.

02) Passed by chemokines

Oncolytic viruses can usually stimulate the local secretion of type I IFN, and some genetically modified OVs can produce more and a wider range of chemokines, and enhance the effect of cytotoxic T cells, DCs, macrophages or other immune cells on the tumor environment. Of infiltration. Combined with CAR-T cell therapy, it has a stronger therapeutic effect.

03) Express Bispecific T Cell Conjugate (BiTE)

OVs infection can stimulate T cell-mediated bystander effect and kill tumor cells that are not infected with OVs. It plays a role in solving the heterogeneity of effectiveness in solving cold tumors and preventing CAR-mediated antigen escape.

04) Tumor-mediated selective surface antigen delivery

How CAR-T cells accurately recognize target tumor antigens has been a challenge so far, and the use of OVs-mediated tumors to selectively express specific surface antigens can enhance the anti-tumor activity of CAR T cell therapy.

05) Current challenges and future directions

In the combined use of CAR-T cell immunotherapy and OVs therapy, the oncolytic virus not only provides a powerful oncolytic effect, but also produces a large number of immune stimulating factors and releases TAA. It helps CAR-T cells and autoimmune cells to accumulate in the tumor area and kill tumor cells.

The mechanism of OVs in stimulating anti-tumor immunity still needs to be further studied. It is necessary to find better methods to enhance the immunogenicity of tumor cells and reduce the immunogenicity of the virus itself.

In short, oncolytic viruses can enhance the infiltration of CAR-T cells in TME and help the killing effect of CAR-T cells.

The design of next-generation CAR-T cells and OVs can be considered comprehensively. Whether this combination therapy is successful in future clinical studies, we will wait and see!

Immunotherapy: Combination therapy of CAR-T cells and oncolytic virus

(source:internet, reference only)

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