Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies

Abstract

Technologies required to generate induced pluripotent stem cells (iPSC) were first described 15 years ago, providing a strong impetus to the field of regenerative medicine. In parallel, immunotherapy has finally emerged as a clinically meaningful modality of cancer therapy. In particular, impressive efficacy has been achieved in patients with selected haematological malignancies using ex vivo expanded autologous T cells engineered to express chimeric antigen receptors (CARs). While solid tumours account for over 90% of human cancer, they currently are largely refractory to this therapeutic approach. Nonetheless, given the considerable innovation taking place worldwide in the CAR field, it is likely that effective solutions for common solid tumours will emerge in the near future. Such a development will create significant new challenges in the scalable delivery of these complex, costly and individualised therapies. CAR-engineered immune cell products that originate from iPSCs offer the potential to generate unlimited numbers of homogeneous, standardised cell products in which multiple defined gene modification events have been introduced to ensure safety, potency and reproducibility. Here, we review some of the emerging strategies in use to engineer CAR-expressing iPSC-derived drug products.

Treatment with Living Drugs: Pharmaceutical Aspects of CAR T Cells

“…While currently CAR T cell products are manufactured starting from peripheral blood T cells, induced pluripotent stem cells (iPSCs) are an alternative source which takes advantage of the unlimited proliferative capacities of iPSCs [99]. A first-of-class hiPSC-derived CAR T cell product (FT819) was generated by reprogramming peripheral blood T cells and targeted insertion of a CD19 CAR into both alleles of the TCR-α (TRAC) locus [100]; FT819 has been translated into clinical exploration [101, 102] with the first patient treated in a phase I study for the treatment of r/r B cell malignancies (NCT04629729).…”

Revolution of CAR Engineering For Next-Generation Immunotherapy In Solid Tumors

“…The rate of CAR expression on iPSC-T cells was relatively lower than that on γδ or αβ T cells, which might reduce tonic signaling. A phase 1 study of iPSC-derived CAR-T cells targeting CD19 has been conducted for leukemia patients ( 164 ).…”

Novel cellular immunotherapies for hematological malignancies: recent updates from the 2021 ASH annual meeting

“…While allogeneic CAR-T or CAR-NK cell therapies are already demonstrating clinical promise, these strategies remain limited due to donor variability and batch to batch heterogeneity [ 97 ]. It is desirable to utilize a single renewable cell source to standardize the manufacture and quality of these novel immunotherapies.…”