Adoptive T-cell therapy is a promising new technique in which T cells are collected from a cancer patient, genetically engineered to express chimeric antigen receptors specifically directed towards antigens on the patient's tumor cells, and are then infused back into the patient. Unfortunately, the approach requires laborious cloning of antigen-specific T cells or the genetic engineering of autologous T cells from each individual patient and is limited to antigens for which patient-specific T cells can be detected, as well as the need to match T-cell specificity to the human leukocyte antigen (HLA) of the recipient patient in cases of orthologous grafts. A facile platform to produce large quantities of antigen-specific T lymphocytes thus represents an unmet need. Production of T lymphocytes from human induced pluripotent stem cells (iPSCs) in vitro is feasible, offering the potential for such scaled-up production.
In the present work, Themeli and colleagues* combine the aspect of unlimited availability of iPSCs with the ability to custom-tailor the specificity of a T cell through the chimeric antigen receptor technology to generate phenotypically defined, functional, and expandable T cells that are genetically targeted to a tumor antigen of interest (Figures A–F). Peripheral blood T lymphocytes from a healthy volunteer were transduced with two retroviral vectors each encoding two of the reprogramming factors KLF4, SOX2, OCT-4, and c-MYC to produce T-cell iPSCs. An iPSC clone was then stably transduced with a bicistronic lentiviral vector encoding a second-generation chimeric antigen receptor specific for CD19, along with an mCherry fluorescent marker.