Viral Delivery of CAR Targets to Solid Tumors Enables Effective Cell Therapy

Amin Aalipour; Fabrice Le Boeuf; Matthew Tang; Surya Murty; Federico Simonetta; Alexander X Lozano; Travis M Shaffer; John C Bell; Sanjiv S Gambhir

doi:10.1016/j.omto.2020.03.018

Viral Delivery of CAR Targets to Solid Tumors Enables Effective Cell Therapy

Mol Ther Oncolytics. 2020 Apr 7:17:232-240. doi: 10.1016/j.omto.2020.03.018. eCollection 2020 Jun 26.

Authors

Amin Aalipour^{1

2}, Fabrice Le Boeuf^{3

4}, Matthew Tang^{3

4}, Surya Murty^{1

2}, Federico Simonetta⁵, Alexander X Lozano^{6

7}, Travis M Shaffer^{2

8}, John C Bell^{3

4}, Sanjiv S Gambhir^{1

2

6

8

9}

Affiliations

¹ Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
⁴ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
⁵ Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Materials Science and Engineering, Stanford University, Stanford, CA 94305, USA.
⁷ Faculty of Medicine, University of Toronto, Toronto, ON MS5 1A8, Canada.
⁸ Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94305, USA.

Abstract

Chimeric antigen receptor (CAR) T cell therapy has had limited efficacy for solid tumors, largely due to a lack of selectively and highly expressed surface antigens. To avoid reliance on a tumor's endogenous antigens, here we describe a method of tumor-selective delivery of surface antigens using an oncolytic virus to enable a generalizable CAR T cell therapy. Using CD19 as our proof of concept, we engineered a thymidine kinase-disrupted vaccinia virus to selectively deliver CD19 to malignant cells, and thus demonstrated potentiation of CD19 CAR T cell activity against two tumor types in vitro. In an immunocompetent model of B16 melanoma, this combination markedly delayed tumor growth and improved median survival compared with antigen-mismatched combinations. We also found that CD19 delivery could improve CAR T cell activity against tumor cells that express low levels of cognate antigen, suggesting a potential application in counteracting antigen-low escape. This approach highlights the potential of engineering tumors for effective adoptive cell therapy.

Keywords: CAR T cells; cell therapy; chimeric antigen receptor; combination immunotherapy; immunotherapy; oncolytic virus; solid tumor; synthetic immunology; tumor engineering; vaccinia virus.

Grants and funding

F30 CA236339/CA/NCI NIH HHS/United States