Adoptive Cell Therapy from the Dish: Potentiating Induced Pluripotent Stem Cells

<b><i>Background:</i></b> The clinical success of autologous adoptive cell therapy (ACT) is substantial but wide application is challenged by the quality and quantity of the patient’s immune cells and the need for personalized manufacturing processes. Induced pluripotent stem cells (iPSCs) can be differentiated into immune effectors and thus provide an alternative, allogeneic cell source for ACT. Here, we compare iPSC-derived immune effectors to their PBMC-derived counterparts and review iPSC-derived ACT products currently under preclinical and clinical development. <b><i>Summary:</i></b> iPSC-derived T cells, NK cells, macrophages, and neutrophils largely mimic their PBMC-derived counterparts in terms of cell-surface marker expression and cytotoxic effector functions. iPSC-derived immune effectors can be engineered with chimeric antigen receptors and other activating receptors to redirect their cytotoxic potential specifically to tumor-associated antigens (TAAs). However, several differences between iPSC- and PBMC-derived immune effectors remain and have inspired additional engineering strategies to enhance the antitumor capacity of iPSC-derived immune effectors. <b><i>Key Messages:</i></b> iPSCs can be engineered to facilitate the generation of immune effectors with homogenous specificity for TAAs and enhanced effector functions. TAA-specific and functionally enhanced iPSC-derived T and NK cells are currently undergoing clinical evaluation in phase 1 trials. Engineered iPSC-derived macrophages and neutrophils are in preclinical development.