Monday, February 26, 2024
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HomeLifestyleONCOTECH: a chimeric oncolytic virus and T cells for cancer immunotherapy

ONCOTECH: a chimeric oncolytic virus and T cells for cancer immunotherapy

Researchers have developed an innovative method known as ONCOTECH to physically bind oncolytic adenoviruses to the surfaces of T cells through antigen-receptor interaction. To achieve this, viruses, which encode a Cas9 system targeting immune checkpoint inhibitor genes, are enclosed in cell membranes containing T cell-specific antigens and administered intravenously to tumors. This combination of virotherapy and cell therapy with ONCOTECH represents a promising translational technology.

The research article, “An oncolytic virus and T cell chimera for cancer immunotherapy.“was published in Nature Biotechnology.

ONCOTECH improves antitumor responses

Among the new forms of immunotherapy for the treatment of cancer, oncolytic virotherapy stands out. Oncolytic viruses can kill tumor cells without spreading to healthy tissues because they replicate only in tumor cells after intratumoral administration, triggering tumor-specific inflammatory responses. However, several challenges are limiting the technology.

Systemic administration of oncolytic viruses is more practical for clinical indications and can easily attack primary and disseminated tumors, although intratumoral administration guarantees direct access to tumor lesions and avoids possible systemic neutralization. However, due to insufficient uptake of the virus by tumor cells, intravascular administration of oncolytic viruses has not shown significant antitumor activity. Another drawback of oncolytic virotherapy is the upregulation of immune checkpoints (such as PD-L1) in cancer and healthy immune cells. Two possible solutions are to combine oncolytic viruses with immune checkpoint inhibitors or to add anti-PD-L1 antibodies. However, oncolytic viruses and immune checkpoint inhibitors still have trouble penetrating tumors; therefore, novel approaches are required to target tumors with these agents.

Researchers from Zhejiang University and the Chinese Academy of Sciences created ONCOTECH. The system is based on oncolytic viruses enclosed in a synthetic biological membrane that carries T cell-specific antigens. T cells physically bind oncolytic viruses to their surfaces through their receptors, which can be TCR or chimeric antigen receptors (CAR). ), without affecting cellular function. With the help of carrier T cells that have recognized tumor-specific antigens, cancer cells can easily release and internalize oncolytic viruses, allowing for targeted viral infection. Oncolytic viruses engineered to express the Cas9 editor can downregulate PD-L1 expression on tumor cells and infiltrate immune cells after infection. This reduces the immunosuppressive tumor microenvironment and improves the effectiveness of T cell therapy and oncolysis in fighting tumors.

Several of the limitations of ONCOTECH must be resolved to proceed with clinical translation in the future. One problem is that tumor antigens on biological membranes can repeatedly stimulate TCRs or CARs, exhausting T cells and impairing their ability to perform effector functions. To combat this, carrier T cells can be engineered to express CARs with dual specificities. Furthermore, it is not currently possible to use ONCOTECH to treat advanced solid tumors with antigen deficiency or loss; However, this is not a problem when treating melanoma, lung cancer, PDAC, or glioblastoma, which are all antigen-expressing tumors. Finally, clinical translation could be hampered by immune incompatibility between the receptor and the cells used to produce vesicles. Future research should focus on developing producer cells compatible with the immune system to avoid possible immunological rejection by patients. This will help avoid detection by host immune cells, such as NK cells, prior to viral infection.

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