Oncolytic virus optimizes CAR-T cell therapy for solid tumors

Sept. 29, 2022

Chimeric antigen receptor (CAR)-T cell therapy has emerged as an effective treatment option for a number of indications since its approval by the Food and Drug Administration (FDA) in 2017. The therapy, however, has limited uses for patients with solid tumors due to challenges with expansion, persistence and trafficking, as well as interaction with the aggressive tumor microenvironment (TME).

"One of the problems is that the CAR-T cells can kill the target cells, but the tumor fights back with a highly immunosuppressive microenvironment," says Richard G. Vile, Ph.D., a cancer researcher at Mayo Clinic in Rochester, Minnesota. "This prevents the T cells from acting properly and killing cancer cells efficiently."

A study published in the April 2022 edition of Science Translation Medicine reports progress in using CAR-T cell therapy for solid tumors. In this study, Dr. Vile and his colleagues used oncolytic viruses to enhance the therapy in murine studies complemented by in vitro models. Specifically, the research team aimed to learn how the native T cell receptors in CAR-T cells could be stimulated using oncolytic virus.

CAR-T cell therapy efficacy improved in vivo

Dr. Vile explains that researchers hoped to use CAR-T cells to deliver the oncolytic virus to tumor cells located in the TME. This would cause an inflammatory environment due to infection by the virus, therefore turning a "cold," or poorly immune infiltrated, tumor into a "hot," or highly infiltrated tumor and inciting response by many cytokines.

"We hoped to deliver the virus to the tumor and that the virus would help to deliver more T cells in return," says Dr. Vile.

In this study, researchers loaded oncolytic virus onto the CAR-T cells in vitro and activated the native T cell receptors in vivo. This regimen was able to cure greater than 80% of mice with subcutaneous melanoma and intracranial glioma, and was observed with two different viruses, vesicular stomatitis virus (VSV) and reovirus. The cure was seen across tumor sites, and with viruses that expressed tumor antigens, VSV and adenovirus.

Differentiation of memory cells

In addition to the immediate impact, the dual-specific CAR-T cells could be reactivated in vivo with a systemic boost of the original virus. This resulted in long-term cures greater than 60 days in mice. It also shows that T cell receptor stimulation can provide an opportunity to enhance CAR-T cell therapy.

Dr. Vile and the research team observed that the CAR-T cells became specific to the virus, behaving not only as CAR-T cells but also as viral T cells. The cells began to differentiate into memory cells and persisted in the mice for much longer than traditional CAR-T cells.

"We saw this added benefit that the CAR-T cells recognized the antigens expressed by the virus," says Dr. Vile. "That meant if we readministered the virus when the tumor started to return, the T cells were reactivated much like in response to a traditional vaccine."

CAR-T cell therapy advances rapidly

The most effective CAR-T cells can persist in the body for a long time. Dr. Vile and his colleagues have seen similar effects in human cells in vitro using this regimen. Further testing on efficacy in humans and eventual clinical trials are necessary.

Currently, CAR-T cell therapy products are available for the treatment of relapsed, refractory B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, multiple myeloma, and B-cell acute lymphoblastic leukemia as soon as patients show lack of response to a second line therapy. Due to recent FDA approvals, patients with large B-cell lymphoma who do not respond to an anthracycline-based front-line chemoimmunotherapy or who show evidence of relapse within 12 months from their last dose of that front-line chemoimmunotherapy may be eligible for CAR-T cell therapy as a second line treatment.

This study and others are among the first to advance this therapy for solid tumors. The field of CAR-T cell therapy is advancing rapidly as researchers aim to learn new applications. Care teams at Mayo Clinic Comprehensive Cancer Center can evaluate patients for potential eligibility based on current availability of CAR-T cell therapy treatment programs and products.

For more information

Evgin L, et al. Oncolytic virus–mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice. Science Translational Medicine. 2022;14:eabn2231.

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