In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB).

ABSTRACT: Human T cells engineered to express a chimeric antigen receptor (CAR) specific for folate receptor-? (FR?) have shown robust antitumor activity against epithelial cancers in vitro but not in the clinic because of their inability to persist and home to tumor in vivo. In this study, CARs were constructed containing a FR?-specific scFv (MOv19) coupled to the T-cell receptor CD3? chain signaling module alone (MOv19-?) or in combination with the CD137 (4-1BB) costimulatory motif in tandem (MOv19-BB?). Primary human T cells transduced to express conventional MOv19-? or costimulated MOv19-BB? CARs secreted various proinflammatory cytokines, and exerted cytotoxic function when cocultured with FR?(+) tumor cells in vitro. However, only transfer of human T cells expressing the costimulated MOv19-BB? CAR mediated tumor regression in immunodeficient mice bearing large, established FR?(+) human cancer. MOv19-BB? CAR T-cell infusion mediated tumor regression in models of metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer. Importantly, tumor response was associated with the selective survival and tumor localization of human T cells in vivo and was only observed in mice receiving costimulated MOv19-BB? CAR T cells. T-cell persistence and antitumor activity were primarily antigen-driven; however, antigen-independent CD137 signaling by CAR improved T-cell persistence but not antitumor activity in vivo. Our results show that anti-FR? CAR outfitted with CD137 costimulatory signaling in tandem overcome issues of T-cell persistence and tumor localization that limit the conventional FR? T-cell targeting strategy to provide potent antitumor activity in vivo.

SUBMITTER: Song DG 

PROVIDER: S-EPMC4140173 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature