Charting new paradigms for CAR-T cell therapy beyond current Achilles heels

Front Immunol. 2024 May 1:15:1409021. doi: 10.3389/fimmu.2024.1409021. eCollection 2024.

Abstract

Chimeric antigen receptor-T (CAR-T) cell therapy has made remarkable strides in treating hematological malignancies. However, the widespread adoption of CAR-T cell therapy is hindered by several challenges. These include concerns about the long-term and complex manufacturing process, as well as efficacy factors such as tumor antigen escape, CAR-T cell exhaustion, and the immunosuppressive tumor microenvironment. Additionally, safety issues like the risk of secondary cancers post-treatment, on-target off-tumor toxicity, and immune effector responses triggered by CAR-T cells are significant considerations. To address these obstacles, researchers have explored various strategies, including allogeneic universal CAR-T cell development, infusion of non-activated quiescent T cells within a 24-hour period, and in vivo induction of CAR-T cells. This review comprehensively examines the clinical challenges of CAR-T cell therapy and outlines strategies to overcome them, aiming to chart pathways beyond its current Achilles heels.

Keywords: Achilles heels; allogeneic universal CAR-T cells; chimeric antigen receptor; immunotherapy; in vivo CAR-T cell.

Publication types

  • Review

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Hematologic Neoplasms / immunology
  • Hematologic Neoplasms / therapy
  • Humans
  • Immunotherapy, Adoptive* / adverse effects
  • Immunotherapy, Adoptive* / methods
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / immunology
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / transplantation
  • Tumor Microenvironment / immunology

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study is supported by the National Natural Science Foundation of China 82104252, Shanghai Pujiang Program 21PJ1415600, Guangdong Basic and Applied Basic Research Foundation 2022A1515010491, Zhongshan Municipal Bureau of Science and Technology, and the foundation from Hubei Provincial Department of Science and Technology Project 2023BCB026.