한빛사논문
Anthony K. Park1,2,3, Yuman Fong3,*, Sang-In Kim3, Jason Yang1, John P. Murad1,2, Jianming Lu3, Brook Jeang1, Wen-Chung Chang1, Nanhai G. Chen3, Sandra H. Thomas4, Stephen J. Forman1,5,* and Saul J. Priceman1,5,*,†
1Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA.
2Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA.
3Department of Surgery, City of Hope, Duarte, CA 91010, USA.
4Department of Clinical and Translational Project Development, City of Hope, Duarte, CA 91010, USA.
5Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
†Corresponding author.
*Co-senior authors.
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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