Synergistic Antitumor Effects of Chimeric Antigen Receptor-Modified T Cells and Oncolytic Virotherapy

Oncolytic vaccinia virus (VV) therapy has shown promise in preclinical models and in clinical studies. However their use has been limited by constraints on delivery and effective tumor targeting. The combination of VV therapy with Chimeric Antigen Receptor-modified T cells (CAR-T cells) might overcome these limitations, since CAR-T cells can direct VV to the tumors. In our previous studies, we have developed a novel T-cell Engager Armed Vaccinia Virus (TEA-VVs) strategy that expresses secretory bispecific antibodies that bind both to CD3 and a tumor cell surface antigen EphA2. We demonstrated that EphA2-TEA-VV displays significantly enhanced antitumor activity by inducing bystander killing of tumor cells that are not infected with virus, compared to non-modified VV. In this study, we aimed to evaluate the efficacy of combination therapy of HER2-CAR-T cells with EphA2-TEA-VV. This combinational therapy should exerts its anti-tumor activity through three mechanisms: i) HER2-CAR-T cells recognize and lyse HER2-positive tumor cells, ii) VV infect, replicate in, and lyse tumor cells, and iii) bi-specific antibody expressed by EphA2-TEA-VV directs T cells to recognize EphA2 and kill tumor cells, overcoming tumor heterogeneity. In our preliminary studies, we demonstrated that EphA2-TEA-VV can effectively infect and replicated in HER2-CAR-T cells. In coculture assays, preinfectin of HER2-CAR-T cells with EphA2-TEA-VV resulted in strongly enhanced killing of HER2+EphA2+ A549 tumor cells. These results illustrate the potential of combining CAR-T cells and TEA-VV for synergistic effects that more effectively treat cancer.