Park et al. selectively infected intractable human solid tumor cells with an oncolytic vaccinia virus (OV19t) encoding a truncated CD19 protein (CD19t) and detected intracellular OV19t and CD19t on tumor cell surfaces prior to OV-mediated tumor lysis. CD19-CAR T cells were activated and secreted IFNγ and IL-2 when co-cultured with OV19-infected tumor cells, killed OV19t-infected tumor cells in vitro, and regressed OV19t-infected tumors in multiple xenograft models. Endogenous and transferred murine (m) CD19-CAR splenic T cells infiltrated and regressed syngeneic s.c. tumors expressing mOV19t-encoded mCD19t.
Contributed by Paula Hochman
ABSTRACT: Chimeric antigen receptor (CAR)-engineered T cell therapy for solid tumors is limited by the lack of both tumor-restricted and homogeneously expressed tumor antigens. Therefore, we engineered an oncolytic virus to express a nonsignaling, truncated CD19 (CD19t) protein for tumor-selective delivery, enabling targeting by CD19-CAR T cells. Infecting tumor cells with an oncolytic vaccinia virus coding for CD19t (OV19t) produced de novo CD19 at the cell surface before virus-mediated tumor lysis. Cocultured CD19-CAR T cells secreted cytokines and exhibited potent cytolytic activity against infected tumors. Using several mouse tumor models, delivery of OV19t promoted tumor control after CD19-CAR T cell administration. OV19t induced local immunity characterized by tumor infiltration of endogenous and adoptively transferred T cells. CAR T cell-mediated tumor killing also induced release of virus from dying tumor cells, which propagated tumor expression of CD19t. Our study features a combination immunotherapy approach using oncolytic viruses to promote de novo CAR T cell targeting of solid tumors.