**10. Conclusions: OV Enhanced CAR T Cell Therapy—And Vice Versa**

In the quest for a systemic, potent anti-tumour therapy, both adoptive (CAR) T cell transfer and oncolytic viruses have enormous curative potential. Both intrinsic and engineered capabilities endow OVs with a unique potential to serve as a platform to enhance adoptive T cell therapy. However, in order to reach their destination, both (CAR) T cells and viruses have to navigate a circulatory highway fraught with diversions, patrols and obstacles. Even if/when they successfully reach the tumour, the TME represents a highly immune-suppressive, neutralizing destination. This neighbourhood is unlikely to appeal to any owner of such highly sophisticated and engineered anti-tumour killing machines (cells or viruses) as a safe and effective parking place. However, tumour infection by OVs has the potential to effect a dramatic make over and convert this hostile, T cell repellent TME into a highly attractive haven, open for business for an influx of CAR T cells. In this respect, the inflammatory profile induced by OV infection, as well as OV-triggered transgene expression, needs to be carefully crafted. Moving forward, models in which the safety and efficacy of combination strategies that intricately engage innate and adaptive immunity are evaluated must account for factors which both recruit and support activated CAR T cell therapies, as well as those compensatory mechanisms which restrain and inhibit the (T cell) immune system. Importantly, a variety of models should be used which, combinatorially, analyze the plethora of factors which may be absent from specific model systems, or which may be present but which are non-reactive in the specific model being tested—such as type I IFN, which binds to species specific IFNAR [133]. Thus, it will be critical to prevent OV infection from simply converting a T cell freezing TME into an incendiary, CAR T-vandalizing, TME. With appropriate design of the levels, nature and timing of inflammatory cytokine expression from OV infection, it will be possible to generate an optimal, climate-controlled environment that nurtures the gentle, valet parking of CAR T cells inside the tumour where the T cells can go on to do their worst against solid tumours. Therefore, we believe that by generating novel designer combinations of paired viruses and engineered T cells it will be possible to create a powerful synergy between adoptive T cell therapies and OV infection, whereby each one enhances the tumour trafficking, selectivity and potency of the other.

**Funding:** Funding provided by the National Institutes of Health (P50 CA210964 and R01CA108961 to R.G.V.), The Richard M. Schulze Family Foundation, Mayo Foundation, The Minnesota Partnership for Biotechnology and Medical Genomics, Shannon O'Hara Foundation, Hyundai Hope on Wheels as well as BC Cancer Research and BC Cancer Foundation (L.E.).

**Acknowledgments:** The authors thank Toni L. Woltman for expert secretarial assistance.

**Conflicts of Interest:** L.E. and R.G.V. are inventors on patent applications related to the use of oncolytic viruses and CAR T cells for the treatment of cancer.
