An oncolytic virus-delivered TGF inhibitor overcomes the immunosuppressive tumor microenvironment

Oncolytic viruses induce tumor lysis and inflame the tumor microenvironment but do not relieve immunosuppressive signals. Engineering oncolytic vaccinia virus to express a potent TGF beta R inhibitor results in local neutralization of TGF beta, increased Treg cell fragility, and superior therapeutic response. While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing immune infiltration and preventing immunosuppression are of critical need. We previously generated alpha PD-1 resistant variants of the murine HNSCC model MEER. While entirely alpha PD-1 resistant, these tumors regress after single dose of oncolytic vaccinia virus (VV). We then generated a VV-resistant MEER line to dissect the immunologic features of sensitive and resistant tumors. While treatment of both tumor types induced immune infiltration and IFN gamma, we found a defining feature of resistance was elevation of immunosuppressive cytokines like TGF beta, which blunted IFN gamma signaling, especially in regulatory T cells. We engineered VV to express a genetically encoded TGF beta RII inhibitor. Inhibitor-expressing VV produced regressions in resistant tumor models and showed impressive synergy with checkpoint blockade. Importantly, tumor-specific, viral delivery of TGF beta inhibition had no toxicities associated with systemic TGF beta/TGF beta R inhibition. Our data suggest that aside from stimulating immune infiltration, oncolytic viruses are attractive means to deliver agents to limit immunosuppression in cancer.