Combination Cancer Immunotherapy: Will Oncolytic Virus Plus CAR-T/NK Cell Therapy Be Killer of Solid

Solid tumors are currently the main cause of cancer incidence and mortality in the world. Although immunotherapies such as PD-1/L1 antibodies, chimeric antigen receptor T cell (CAR-T), and oncolytic viruses (OVs) have shown great promise in cancer treatment in recent years, there are still certain challenges in the treatment of solid tumors, such as poor drug effects, and tumor microenvironment (TME) limitations.

Therefore, in order to achieve better treatment effects of solid tumors, combination therapy is becoming one of the important and mainstream research directions. Among them, OV combined with CAR-T and other cell therapies have gradually emerged in the international arena. For example, published articles from City of Hope, Mustang Bio and Mayo Medical Center all show OVs and CAR-T cells have the potential of synergy and can enhance the anti-tumor effect.

• Oncolytic Virus Combined with CAR-T Therapy

OVs can selectively infect tumor cells, replicate in them in large quantities and eventually lyse tumor cells, while at the same time release a large amount of tumor antigens and improve the TME. There is clinical evidence that OVs can enhance tumor response rates to immune regulatory checkpoint inhibitors, CAR-T cells and other immunotherapies, and are ideal to be combined treatment strategies.

CAR-T cell therapy is currently one of the hottest research directions in the field of tumor cell immunotherapy. It has achieved great success in hematological tumors. However, in the treatment of solid tumors, CAR-T cell therapy still faces certain challenges. On one hand, solid tumors have limited targets for CAR-T cells, and on the other hand, solid tumors have a strong protective barrier, that is, the immunosuppressive TME, which makes it difficult for CAR-T cells to survive, amplify and kill tumors.

• Advantages of Oncolytic Virus Combined with CAR-T Therapy

1. Several OVs have been proved to be safe and effective in clinical trials, and CAR-T cells have also been successfully marketed products;
2. OVs can selectively infect and replicate in tumor cells, lyse tumor cells to release tumor antigens, so as to reduce the delivery of CAR to healthy tissues;
3. There is evidence that OVs can readjust the immunosuppressive TME of solid tumors into a microenvironment that is more conducive to T cell activity.

• Research on Combination of Oncolytic Virus and CAR-T therapy

Several institutions started research on the combination therapy of OV and CAR-T cells a few years ago. Recently, a research team from City of Hope published an article about OV combined with CAR-T cell therapy to successfully target and eradicate solid tumors on Science Translational Medicine.

Studies have shown that when the virus, OV19t, which makes cancer cells express a shortened version of CD19 (CD19t), is used in combination with CD19 CAR-T, cancer cells are widely killed; OV19t and CD19 CAR-T produced a strong synergistic effect and cured more than half of the mice, with about 60% of the mice had a complete remission, while only 22% of the mice treated with OV19t alone had tumor regression. The research team is expected to first evaluate the safety of OV19t. If it proves to be safe and effective, it will advance the clinical study of OV19t combined with CD19 CAR-T cell therapy in 2022. It can be expected that after this breakthrough research report, more and more teams and institutions will be interested in the combination therapy.

• From CAR-T to CAR-NK

It is worth noting that related studies have also found the potential of the combination of OVs and CAR-NK cells. CAR-NK cells are referred to as the advanced version of CAR-T. T cells are replaced with innate immune cells-NK cells. NK (natural killer) cells can identify target cells, perform a rapid immune response, and enhance the tumor killing effect of CAR cell therapy without antibodies or major histocompatibility complex (MHC).

In theory, the combination of CAR-NK cells and OV also has a strong synergistic effect. This strategy is still in the pre-clinical research stage, but according to existing research articles and data, this combination therapy has great potential in the treatment of solid tumors.

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