From bench to bedside: the history and progress of CAR T cell therapy

Abstract

Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.

Keywords: TCR - T cell receptor; cancer immunotherapy; chimeric antigen receptor (CAR T); cytokine release syndrome; tumor burden.

Figure 1

The differences in tumor antigen recognition between conventional TCRs and synthetic CARs. (A) TCR recognition of tumor antigens is restricted by MHC complex molecules, and the suboptimal efficiency of cancer cell killing by conventional T cells may be due in part to the lack of CD80/86 expression on tumor cells. The CD8 coreceptor has been omitted from the illustration for purpose of simplicity. (B) Synthetic CARs recognize tumor-associated antigens on the surface of cancer cells through the single-chain variable fragment (scFv) domain. These interactions then simultaneously activate both the CD3-mediated primary signal and the CD28/4-1BB-mediated secondary signal in T cells. (C) The scFv domain is derived from a monoclonal antibody and consists of the variable regions from the heavy chain (V_H) and light chain (V_L) linked by a flexible linker sequence.

Figure 2

The timeline of key milestones in the development of CAR T cell therapy.