Generation of hypoimmunogenic T cells from genetically engineered allogeneic human induced pluripotent stem cells

Nat Biomed Eng. 2021 May;5(5):429-440. doi: 10.1038/s41551-021-00730-z. Epub 2021 May 17.

Abstract

Avoiding the immune rejection of transplanted T cells is central to the success of allogeneic cancer immunotherapies. One solution to protecting T-cell grafts from immune rejection involves the deletion of allogeneic factors and of factors that activate cytotoxic immune cells. Here we report the generation of hypoimmunogenic cancer-antigen-specific T cells derived from induced pluripotent stem cells (iPSCs) lacking β2-microglobulin, the class-II major histocompatibility complex (MHC) transactivator and the natural killer (NK) cell-ligand poliovirus receptor CD155, and expressing single-chain MHC class-I antigen E. In mouse models of CD20-expressing leukaemia or lymphoma, differentiated T cells expressing a CD20 chimeric antigen receptor largely escaped recognition by NKG2A+ and DNAM-1+ NK cells and by CD8 and CD4 T cells in the allogeneic recipients while maintaining anti-tumour potency. Hypoimmunogenic iPSC-derived T cells may contribute to the creation of off-the-shelf T cell immunotherapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Cell Differentiation
  • Cell Line
  • Gene Knockout Techniques
  • Genetic Engineering
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / immunology
  • Leukemia / immunology
  • Leukemia / therapy*
  • Lymphoma / immunology
  • Lymphoma / therapy*
  • Male
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism
  • Receptors, Virus / genetics*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation*
  • Xenograft Model Antitumor Assays
  • beta 2-Microglobulin / genetics*

Substances

  • Antigens, Differentiation, T-Lymphocyte
  • CD226 antigen
  • NK Cell Lectin-Like Receptor Subfamily C
  • Receptors, Virus
  • beta 2-Microglobulin
  • poliovirus receptor