Oncolytic virus and CAR-T cell therapy in solid tumors

Abstract

Adoptive immunotherapy with T cells, genetically modified to express a tumor-reactive chimeric antigen receptor (CAR), is an innovative and rapidly developing life-saving treatment for cancer patients without other therapeutic opportunities. CAR-T cell therapy has proven effective only in hematological malignancies. However, although by now only a few clinical trials had promising outcomes, we predict that CAR-T therapy will eventually become an established treatment for several solid tumors. Oncolytic viruses (OVs) can selectively replicate in and kill cancer cells without harming healthy cells. They can stimulate an immune response against the tumor, because OVs potentially stimulate adaptive immunity and innate components of the host immune system. Using CAR-T cells along with oncolytic viruses may enhance the efficacy of CAR-T cell therapy in destroying solid tumors by increasing the tumor penetrance of T cells and reducing the immune suppression by the tumor microenvironment. This review describes recent advances in the design of oncolytic viruses and CAR-T cells while providing an overview of the potential combination of oncolytic virotherapy with CAR-T cells for solid cancers. In this review, we will focus on the host-virus interaction in the tumor microenvironment to reverse local immunosuppression and to develop CAR-T cell effector function.

Keywords: CAR T cells; cancer; immunotherapy; oncolytic viruses; solid tumor.

Figure 1

The figure illustrates that the heightened oncolytic immunogenicity is a distinctive feature of OVs. As OVs induce the lysis of tumor cells, they release a combination of viral progeny, tumor-specific antigens (TSAs), pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), orchestrating immunogenic cell death (ICD). This intricate process not only activates innate immunity, with collaboration between immune cells for effective tumor clearance. This leads to the release of inflammatory factors and chemokines (CXCL9, CXCL10, HMGB1), ultimately reversing the immunosuppressive characteristics of the tumor microenvironment (TME). Created with BioRender.com.

Figure 2

The figure illustrates the synergistic combination of CAR-T cells and oncolytic viruses. (A) CAR-T cells encounter various challenges in solid tumors, including an immunosuppressive environment that may lead to T cell dysfunction and treatment failure. (B) Administering oncolytic viruses for cancer treatment before CAR-T cell therapy leads to tumor debulking, immunogenic cell death, and a reversal of tumor immunosuppression. (C) In a collaborative effort, the engineered oncolytic viruses may transform the immunologically “cold” tumor into a “hot” tumor, exerting an upgraded and more powerful antitumor immunity. Oncolytic viruses can be genetically modified to deliver therapeutic transgenes into the tumor microenvironment, boosting T-cell effector functions. Combining CAR-T cells with oncolytic viruses armed with cytokines, chemokines, BiTEs, or immune checkpoint inhibitors has demonstrated enhanced therapeutic outcomes. Created with BioRender.com.