Oncolytic virus-derived type I interferon restricts CAR T cell therapy

Abstract

The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNβ infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNβ. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.

Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas

“…Unexpectedly, another pre-clinical study demonstrated that OV-associated type I IFN response has negative effect on CAR T cell therapy (289). The inflammatory environment generated by the oncolytic viruses and the remodeling of the tumor microenvironment neither helped in recruiting CAR T cells nor enhanced their functionality.…”

IFN-I-tolerant oncolytic Semliki Forest virus in combination with anti-PD1 enhances T cell response against mouse glioma

“…A virus-induced IFN-I response can also negatively affect anti-tumor T cells, as reported recently by Evgin et al. 35 using a combination of oncolytic vesicular stomatitis virus (VSV) and chimeric antigen receptor (CAR) T cell therapy in a mouse melanoma model. Herein, we report that systemically administered oncolytic SFV-AM6-124T in combination with anti-PD1 results in increased anti-tumor CD8 + infiltration in an orthotopic mouse GL261 model.…”

Type I interferon signaling limits viral vector priming of CD8+ T cells during initiation of vitiligo and melanoma immunotherapy

“…A recent study reported increased tumor regression after IFNaR blockade during oncolytic virus therapy in combination with adoptive T‐cell therapy in mice (Walsh et al., 2019). Another report revealed that type I IFN following oncolytic virus infection reduced the efficacy of a combination therapy with CAR T cells, highlighting an important observation that type I IFN production following virus infection can suppress the anti‐tumor response (Evgin et al., 2020). Our findings suggest that blockade of IFNaR during vaccinia virus vaccine for cancer immunotherapy may enhance both immunogenicity and persistence of the vector, thus improving vaccine efficacy, and may induce long‐term benefits for tumor eradication.…”