CAR-expressing T cells generated from iPSCs are similar to γδ T cells and suppress tumor growth.

  • Major finding: CAR-expressing T cells generated from iPSCs are similar to γδ T cells and suppress tumor growth.

  • Approach: CD19-specific human T cells were generated via differentiation of iPSCs expressing the 19-28z CAR.

  • Impact: This strategy may enable enhanced production of antigen-specific T cells for cancer therapy.

The broad use of adoptive T-cell transfer for cancer immunotherapy has been limited by the ability to rapidly generate sufficient numbers of tumor antigen-specific autologous or donor-matched T cells. Findings from recent studies have suggested that in vitro differentiation of induced pluripotent stem cells (iPSC), which can be established via expression of reprogramming transcription factors, may represent an alternative approach to generate human T cells, but the therapeutic utility of these cells is unproven. To facilitate the production of tumor antigen-specific iPSC-derived T cells, Themeli and colleagues expressed a second-generation chimeric antigen receptor (CAR) targeting the B-cell antigen CD19 and containing a CD28 costimulatory domain (19-28z), which has shown antitumor activity against B-cell malignancies, in iPSC clones generated from human peripheral blood T lymphocytes. Differentiation of 19-28z+ iPSCs produced T cells that were phenotypically similar to the innate γδ T-cell subset and exhibited an effector memory phenotype. These CAR-modified T cells expressed T-cell activation markers and secreted type 1 cytokines, including TNF-α, IFN-γ, and interleukin-2 in response to the CD19 antigen, indicative of a functional response and antigen specificity. Furthermore, stimulation with CD19 efficiently induced the expansion of 19-28z+ iPSC-derived T cells without compromising their functional activity or affecting the upregulation of natural cytotoxicity receptors. Expanded CAR-engineered iPSC-derived T cells exhibited cytotoxic activity and specifically targeted CD19-expressing lymphoma cells for elimination in vitro and inhibited lymphoma xenograft growth in vivo, resulting in tumor regression and prolonged survival of tumor-bearing mice after T-cell infusion, similar to peripheral γδ T cells transduced to express 19-28z. These findings validate this approach as a potential strategy to improve the generation of antigen-specific therapeutic T cells for cancer immunotherapy.

Themeli M, Kloss CC, Ciriello G, Fedorov VD, Perna F, Gonen M, et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol 2013 Aug 11 [Epub ahead of print].