My research works to understand how the unique immunomodulatory properties of different viruses impact the clinical outcome of cancer immunotherapies and influence the balance between autoimmunity and tumor regression. I have focused on oncolytic viruses (OVs), a subgroup of viruses that selectively replicate in tumor cells. OVs are derived from an array of virus families with varied replication strategies and so, can have very different effects on the immune system1. My studies have focused on two OVs with distinctly different inflammatory profiles. Vesicular stomatitis virus (VSV) induces robust inflammation, both locally and systemically, whereas vaccinia virus (VacV) encodes viral proteins with direct inhibitory effects on inflammation. I have found that both OVs show a potent ability to stimulate tumor-specific T cells when implemented as cancer vaccines, while facilitating penetration of those T cells into the core of solid tumors and supporting their killing function2. Thus, OV cancer vaccines levy multimodal effects on the tumor, inducing T cell responses and rapid tumor regression.
Looking more closely at how OVs modulate inflammation to degenerate distinct therapeutic outcomes, I have found that systemic inflammation induced by VSV can be detrimental. More specifically, high levels of T1IFN stimulated by VSV was responsible for autoimmune toxicity tied to therapeutic success when expression of the tumor targeted antigen was shared by normal cells. T1IFN upregulated MHC I expression on normal cells and drove autoimmunity in this context by making them more visible to anti-tumor T cells. By using a blocking antibody to modulate T1IFN signaling during VSV vaccination, I was able to suppress MHC I upregulation on normal cells and eliminate autoimmune toxicity tied to the therapeutic efficacy of treatment3. In addition, by leveraging the T1IFN neutralizing effect of B18R, an immunomodulatory protein encoded by VacV, I was able to decouple toxicity from therapeutic efficacy and demonstrate the unique utility of this vaccine vector3. Furthermore, I have also found that blockade of TIFN inhibits upregulation of several immunosuppressive ligands, preventing mechanism of T cell exhaustion in a multimodal with a single treatment4.
1. Burchett, R., Walsh, S., Wan, Y. & Bramson, J. L. A rational relationship: Oncolytic virus vaccines as functional partners for adoptive T cell therapy. Cytokine Growth Factor Rev 56, 149–159 (2020).
2. Walsh, S. R. et al. Endogenous T cells prevent tumor immune escape following adoptive T cell therapy. Journal of Clinical Investigation 129, (2019).
3. Walsh, S. R. et al. Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity. Journal of Clinical Investigation 129, (2019).
4. El-Sayes, N. et al. IFNAR blockade synergizes with oncolytic VSV to prevent virus-mediated PD-L1 expression and promote antitumor T cell activity. Mol Ther Oncolytics 25, 16–30 (2022).