A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy

Nat Commun. 2021 Jan 18;12(1):430. doi: 10.1038/s41467-020-20658-3.

Abstract

Clinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of "off-the-shelf" T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce "off-the-shelf" and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques / methods*
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Chemokine CXCL12 / metabolism
  • Culture Media / metabolism
  • Culture Media / pharmacology
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Immunotherapy, Adoptive / methods*
  • Induced Pluripotent Stem Cells / physiology*
  • Mice
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Pyridines / pharmacology
  • Receptors, Chimeric Antigen / immunology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / transplantation*
  • Xenograft Model Antitumor Assays

Substances

  • CXCL12 protein, human
  • Chemokine CXCL12
  • Culture Media
  • Imidazoles
  • Pyridines
  • Receptors, Chimeric Antigen
  • SB 203580