The Pluripotent Path to Immunotherapy

Abstract

Adoptive cell therapy (ACT) enhances the patient's own immune cells’ ability to identify and eliminate cancer cells. Several immune cell types are currently being applied in autologous ACT, including T cells, natural killer (NK) cells, and macrophages. The cells’ inherent antitumor capacity can be used, or they can be targeted toward tumor-associated antigen through expression of a chimeric antigen receptor (CAR). Although CAR-based ACT has achieved great results in hematologic malignancies, the accessibility of ACT is limited by the autologous nature of the therapy. Induced pluripotent stem cells (iPSCs) hold the potential to address this challenge, because they can provide an unlimited source for the in vitro generation of immune cells. Various immune subsets have been generated from iPSC for application in ACT, including several T-cell subsets (αβT cells, mucosal-associated invariant T cells, invariant NKT [iNKT] cells, and γδT cells), as well as NK cells, macrophages, and neutrophils. iPSC-derived αβT, NK, and iNKT cells are currently being tested in phase I clinical trials. The ability to perform (multiplexed) gene editing at the iPSC level and subsequent differentiation into effector populations not only expands the arsenal of ACT but allows for development of ACT utilizing cell types which cannot be efficiently obtained from peripheral blood or engineered and expanded in vitro.