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.
Author Info: (1) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. Irell and Manella Graduate School of Biological Sciences, City of Hope, Du
Author Info: (1) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA. Department of Surgery, City of Hope, Duarte, CA 91010, USA. (2) Department of Surgery, City of Hope, Duarte, CA 91010, USA. (3) Department of Surgery, City of Hope, Duarte, CA 91010, USA. (4) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. (5) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA. (6) Department of Surgery, City of Hope, Duarte, CA 91010, USA. (7) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. (8) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. (9) Department of Surgery, City of Hope, Duarte, CA 91010, USA. (10) Department of Clinical and Translational Project Development, City of Hope, Duarte, CA 91010, USA. (11) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (12) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. spriceman@coh.org. Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
