Genome Engineering for Next-Generation Cellular Immunotherapies

Biochemistry. 2023 Dec 19;62(24):3455-3464. doi: 10.1021/acs.biochem.2c00340. Epub 2022 Aug 5.

Abstract

Over the past decade, cellular immunotherapies such as CAR-T, TCR-T, and NK cell therapies have achieved tremendous success in cancer treatment. However, various challenges and obstacles remain, including antigen escape, immunosuppression in the tumor microenvironment, toxicities, and on-target off-tumor effects. Recent strategies for overcoming these roadblocks have included the use of genome engineering. Multiplexed CRISPR-Cas and synthetic biology approaches facilitate the development of cell therapies with higher potency and sophisticated modular control; they also offer a toolkit for allogeneic therapy development. Engineering approaches have targeted genetic modifications to enhance long-term persistence through cytokine modulation, knockout of genes mediating immunosuppressive signals, and genes such as the endogenous TCR and MHC-I that elicit adverse host-graft interactions in an allogeneic context. Genome engineering approaches for other immune cell types are also being explored, such as CAR macrophages and CAR-NK cells. Future therapeutic development of cellular immunotherapies may also be guided by novel target discovery through unbiased CRISPR genetic screening approaches.

Publication types

  • Review
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines
  • Gene Editing
  • Humans
  • Immunotherapy*
  • Immunotherapy, Adoptive
  • Neoplasms* / genetics
  • Neoplasms* / therapy
  • Receptors, Antigen, T-Cell
  • Tumor Microenvironment

Substances

  • Cytokines
  • Receptors, Antigen, T-Cell