The Emerging Role of Induced Pluripotent Stem Cells as Adoptive Cellular Immunotherapeutics

SIMPLE SUMMARY: Adoptive cell therapy (ACT) is an innovative approach to combat cancer and infectious diseases using specialised immune cells, such as chimeric antigen receptor T-cells (CAR-Ts), tumour-infiltrating lymphocytes (TILs) and virus-specific T-cells (VSTs). Such therapies are manufactured individually for each patient and can be negatively affected by poor cell quality, often impaired by prior treatments, age, and complex manufacturing. To overcome this, this field is assessing the potential of creating cell therapies from “fit” donors to provide off-the-shelf treatment options. Induced pluripotent cells (iPSCs) have renewable characteristics and offer a solution towards off-the-shelf therapy. iPSCs can be used as an unlimited source to derive different immune cells, including natural killer (NK) cells and T-cells. iPSCs can be further genetically modified and used create different ACTs. In this review, we describe the methodologies for generating such cell therapies from iPSCs and discuss the current advances and challenges with a focus on CAR-T/NK-, TIL- and VST-based therapies. ABSTRACT: Adoptive cell therapy (ACT) has transformed the treatment landscape for cancer and infectious disease through the investigational use of chimeric antigen receptor T-cells (CAR-Ts), tumour-infiltrating lymphocytes (TILs) and viral-specific T-cells (VSTs). Whilst these represent breakthrough treatments, there are subsets of patients who fail to respond to autologous ACT products. This is frequently due to impaired patient T-cell function or “fitness” as a consequence of prior treatments and age, and can be exacerbated by complex manufacturing protocols. Further, the manufacture of autologous, patient-specific products is time-consuming, expensive and non-standardised. Induced pluripotent stem cells (iPSCs) as an allogeneic alternative to patient-specific products can potentially overcome the issues outlined above. iPSC technology provides an unlimited source of rejuvenated iPSC-derived T-cells (T-iPSCs) or natural killer (NK) cells (NK-iPSCs), and in the context of the growing field of allogeneic ACT, iPSCs have enormous potential as a platform for generating off-the-shelf, standardised, “fit” therapeutics for patients. In this review, we evaluate current and future applications of iPSC technology in the CAR-T/NK, TIL and VST space. We discuss current and next-generation iPSC manufacturing protocols, and report on current iPSC-based adoptive therapy clinical trials to elucidate the potential of this technology as the future of ACT.