CRISPR-Cas gene knockouts to optimize engineered T cells for cancer immunotherapy

Cancer Gene Ther. 2024 Aug;31(8):1124-1134. doi: 10.1038/s41417-024-00771-x. Epub 2024 Apr 12.

Abstract

While CAR-T and tgTCR-T therapies have exhibited noteworthy and promising outcomes in hematologic and solid tumors respectively, a set of distinct challenges remains. Consequently, the quest for novel strategies has become imperative to safeguard and more effectively release the full functions of engineered T cells. These factors are intricately linked to the success of adoptive cell therapy. Recently, CRISPR-based technologies have emerged as a major breakthrough for maintaining T cell functions. These technologies have allowed the discovery of T cells' negative regulators such as specific cell-surface receptors, cell-signaling proteins, and transcription factors that are involved in the development or maintenance of T cell dysfunction. By employing a CRISPR-genic invalidation approach to target these negative regulators, it has become possible to prevent the emergence of hypofunctional T cells. This review revisits the establishment of the dysfunctional profile of T cells before delving into a comprehensive summary of recent CRISPR-gene invalidations, with each invalidation contributing to the enhancement of engineered T cells' antitumor capacities. The narrative unfolds as we explore how these advancements were discovered and identified, marking a significant advancement in the pursuit of superior adoptive cell therapy.

Publication types

  • Review

MeSH terms

  • Animals
  • CRISPR-Cas Systems*
  • Gene Editing / methods
  • Gene Knockout Techniques / methods
  • Humans
  • Immunotherapy / methods
  • Immunotherapy, Adoptive* / methods
  • Neoplasms* / genetics
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / immunology
  • Receptors, Chimeric Antigen / metabolism
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / metabolism

Substances

  • Receptors, Chimeric Antigen