Research ArticleCancer

Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors

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Science Translational Medicine  02 Sep 2020:
Vol. 12, Issue 559, eaaz1863
DOI: 10.1126/scitranslmed.aaz1863

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Virus helps drive CAR T cells

Chimeric antigen receptor (CAR) T cells are engineered to recognize specific antigens on tumor cells. In some cases, such as with the B cell antigen CD19, a naturally occurring antigen presents an effective target. In most cases, however, there is no antigen that is uniformly present on tumor cells but not normal tissues. Park et al. designed an oncolytic virus that delivers CD19 to tumor cells, which can then be targeted with CD19-specific CAR T cells. Killed tumor cells release additional copies of the virus, propagating CD19 expression to adjacent tumor cells. This combination strategy showed promising results in multiple mouse models of cancer.

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.

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