American Association for Cancer Research
Browse
23266066cir170314-sup-185067_3_supp_4612708_p58106.pdf (584.87 kB)

Supplementary Figures 1 and 2 from Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus–Driven Production of a Bispecific T-cell Engager

Download (584.87 kB)
journal contribution
posted on 2023-04-03, 22:44 authored by Anna Wing, Carlos Alberto Fajardo, Avery D. Posey, Carolyn Shaw, Tong Da, Regina M. Young, Ramon Alemany, Carl H. June, Sonia Guedan

S1. Therapeutic index of EGFR-targeting CART cells and the OAd-BiTE. S2. The Combination of FR-CART cells and OAd-BiTE mediates tumor regression in mice bearing pancreatic xenograft tumors.

Funding

Penn Skin Biology and Diseases Resource-based Center

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Find out more...

History

ARTICLE ABSTRACT

T cells expressing chimeric antigen receptors (CART) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors. We report that CART cells targeting the folate receptor alpha (FR-α) successfully infiltrated preestablished xenograft tumors but failed to induce complete responses, presumably due to the presence of antigen-negative cancer cells. We demonstrated that OAd-BiTE–mediated oncolysis significantly improved CART-cell activation and proliferation, while increasing cytokine production and cytotoxicity, and showed an in vitro favorable safety profile compared with EGFR-targeting CARTs. BiTEs secreted from infected cells redirected CART cells toward EGFR in the absence of FR-α, thereby addressing tumor heterogeneity. BiTE secretion also redirected CAR-negative, nonspecific T cells found in CART-cell preparations toward tumor cells. The combinatorial approach improved antitumor efficacy and prolonged survival in mouse models of cancer when compared with the monotherapies, and this was the result of an increased BiTE-mediated T-cell activation in tumors. Overall, these results demonstrated that the combination of a BiTE-expressing oncolytic virus with adoptive CART-cell therapy overcomes key limitations of CART cells and BiTEs as monotherapies in solid tumors and encourage its further evaluation in human trials. Cancer Immunol Res; 6(5); 605–16. ©2018 AACR.