Mechanisms of resistance to chimeric antigen receptor-T cells in haematological malignancies

  • Nat Rev Drug Discov. 2023 Dec;22(12):976-995. doi: 10.1038/s41573-023-00807-1.
Marco Ruella  #  1 ,  Felix Korell  #  2  3 ,  Patrizia Porazzi  #  1 ,  Marcela V Maus  4  5
Affiliations
  • 1. Division of Hematology and Oncology and Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA.
  • 2. Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  • 3. Harvard Medical School, Boston, MA, USA.
  • 4. Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Boston, MA, USA. [email protected].
  • 5. Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 37907724 DOI: 10.1038/s41573-023-00807-1
Abstract

Chimeric antigen receptor (CAR)-T cells have recently emerged as a powerful therapeutic approach for the treatment of patients with chemotherapy-refractory or relapsed blood cancers, including acute lymphoblastic leukaemia, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma and multiple myeloma. Nevertheless, resistance to CAR-T cell therapies occurs in most patients. In this Review, we summarize the resistance mechanisms to CAR-T cell immunotherapy by analysing CAR-T cell dysfunction, intrinsic tumour resistance and the immunosuppressive tumour microenvironment. We discuss current research strategies to overcome multiple resistance mechanisms, including optimization of the CAR design, improvement of in vivo T cell function and persistence, modulation of the immunosuppressive tumour microenvironment and synergistic combination strategies.