Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors

Abstract

Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored.

Keywords: CAR (chimeric antigen receptor); CRS (cytokine release syndrome); ICANS (immune effector cell-associated neurotoxicity syndrome); T cell exhaustion; antigen; efficacy; hematological malignancy; heterogeneity; safety; solid tumor.

Figure 1

Production, application, and activity monitoring of CAR T-cells.

Figure 2

Active CAR T-cell therapies developed in 2022 and 2021. (a) A total of 1432 active CAR T-cell therapies have been developed in 2022, including preclinical research (854), phase I (314), phase II (243), phase III and market trials of 21. (b) A total of 1150 active CAR T-cell therapies were developed in 2021, including 633 preclinical research, 279 phase I, 227 phase II, 11 phase III and market trials.

Figure 3

Active CAR T-cell therapies in leukemia in 2022. A total of 134 CAR T-cell trials were conducted in 2022 based on different targets.

Figure 4

Number of active CAR T-cell trials investigated in 2022. Based on the different antigenic targets, 4 CAR T-cell products are anti-HER2, 6 CAR T-cell products are anti-4 MSLN, 7 CAR T-cell products are anti-4 GPC, 10 CAR T-cell products are anti-EGFR.

Figure 5

The efficacy and safety of CAR T-cell therapy in the treatment of solid tumors are always at opposite ends of the scale. (a) the balance between safety and efficacy, (b) higher safety, lower efficacy: safety improves always at the expense of efficacy, (c) higher efficacy, lower safety, efficacy improves always at the expense of safety.

Figure 6

Possible reasons for the failure to sustain remission after CAR T-cell therapies. (1) CAR T-cell products: CAR T-cell product from some patients may not be successfully manufactured due to T cell problems (e.g., autologous T cells obtained from the patients after chemotherapy), or the produced CAR T-cells may not expand adequately either during in vitro culture or after infusion in vivo. Limited persistence of CAR T-cells in other patients is a potential mechanism for disease recurrence. (2). Antigen expression: The absence or downregulation of antigens on the tumor cell surfaces, allows antigen escape as a mechanism of resistance to CAR T-cell therapy. (3). Severe toxicities of CAR T-cell therapy: The fatal toxicity of CAR T-cell therapy (e.g., CRS and/or neurotoxicity) prevents a small percentage of patients benefit from the potential therapeutic of CAR T-cell therapy. (4). Optimization of CAR T-cell therapy in clinical application: For the treatment of the patients with pediatric lymphoma, and solid tumors, CAR T- cell therapy need to be further optimized.