A combination therapy of oncolytic viruses and chimeric antigen receptor T cells: a mathematical model proof-of-concept.

Combining chimeric antigen receptor T (CAR-T) cells with oncolytic viruses (OVs) has recently emerged as a promising treatment approach in preclinical studies that aim to alleviate some of the barriers faced by CAR-T cell therapy. In this study, we address by means of mathematical modeling the main question of whether a single dose or multiple sequential doses of CAR-T cells during the OVs therapy can have a synergetic effect on tumor reduction. To that end, we propose an ordinary differential equations-based model with virus-induced synergism to investigate potential effects of different regimes that could result in efficacious combination therapy against tumor cell populations. Model simulations show that, while the treatment with a single dose of CAR-T cells is inadequate to eliminate all tumor cells, combining the same dose with a single dose of OVs can successfully eliminate the tumor in the absence of virus-induced synergism. However, in the presence of virus-induced synergism, the same combination therapy fails to eliminate the tumor. Furthermore, it is shown that if the intensity of virus-induced synergy and/or virus oncolytic potency is high, then the induced CAR-T cell response can inhibit virus oncolysis. Additionally, the simulations show a more robust synergistic effect on tumor cell reduction when OVs and CAR-T cells are administered simultaneously compared to the combination treatment where CAR-T cells are administered first or after OV injection. Our findings suggest that the combination therapy of CAR-T cells and OVs seems unlikely to be effective if the virus-induced synergistic effects are included when genetically engineering oncolytic viral vectors.