Patrick Nicholson

Background: CAR-T Cells is an advancing field of molecular medicine whereby T-Cells are engineered to combat specific forms of cancer. The structure of CAR-T Cells include a single chain variable antibody fragment (scFv) and an intracellular signaling motif, which itself consists of the CD3ζ activation domain fused with one or more costimulatory domains.¹ Currently CAR-T Cells are known for their treatment of B-Cell lymphoma, as this is what got the treatment approved by the FDA.² However, limitations do exist that decrease the efficacy of CAR-T Cell therapy, such as design flaws that allow only a single antigen to be recognized by a single CAR-T Cell, T-Cell exhaustion³ and overexpression of Indoleamine 2,3-dioxygenase 1 (IDO1).² There are also side effects, such as cytokine release syndrome⁴ and neurotoxicity⁵, that dissuade physicians from prescribing CAR-T Cell therapy.

Objective:  In this narrative review, we explored the efficacy of CAR-T Cell therapy.

Search Methods: The PubMed online database was searched from 2018-2024 utilizing the following key phrases “CAR-T Cells”, “CAR-T Cell Resistance” and “CAR-T Cell Structure”.

Results: Studies show that CAR-T Cells are designed to only be able to recognize a single antigen of a tumor, meaning if that particular tumor antigen disappears or a cancer is defined by multiple different antigens, CAR-T Cells will not be able to identify and eliminate said cancer.⁶ However, the use of a receptor, such as NKG2D, that can respond to multiple different antigens can increase tumor removal efficiency, as seen by an overall increase in cytokines released by the use of NKG2D in comparison to normal T-Cells.⁶ T-Cell exhaustion involves excessive secretion of checkpoint proteins, specifically PD-1, that slow differentiation and development of T-Cells to take away the CAR-T Cell’s ability to kill its target cells (tumor cells).⁷ It was also found that IDO1 lowers tryptophan levels, which are needed by dendritic cells to properly function, meaning even if CAR-T Cells can operate, if they can’t activate other immune cells, CAR-T Cell therapy would be ineffective.² Finally, it was found that AT-rich interactive domain-containing protein 5A (ARID5A) protects IDO1 mRNA, allowing it to better inhibit CAR-T Cell therapy.² It was found cytokine release syndrome (CRS) was caused by CAR-T Cells releasing a large amount of granzyme B, which activates caspase 3, which activates the GSDME pathway in B-cells leading to pyroptosis factors and the release of proinflammatory cytokines.⁴ The release of angiopoietin 2 (ANG2) and von Willebrand factor (vWf) lead to increased vascular permeability, then coagulopathy and finally neurotoxicity.⁵

Conclusions: CAR-T Cell therapy is a promising therapy for cancer because of its specificity, but issues must be addressed to improve its efficacy such as multi-tumor antigen recognition, decreasing checkpoint protein production, lowering IDO1 and ARID5A levels and preventing excessive release of cytokines and vWf that can cause CRS and neurotoxicity respectively.

Works Cited:

1. Eugene-Norbert M, Cuffel A, Riou G, et al. Development of optimized cytotoxicity assays for assessing the antitumor potential of CAR-T cells. Journal of Immunological Methods. 2024;525. doi:10.1016/j.jim.2023.113603
2. Wu D, Wang G, Wen S, Liu X, He Q. ARID5A stabilizes Indoleamine 2,3-dioxygenase expression and enhances CAR T cell exhaustion in colorectal cancer. Transl Oncol. 2024;42:101900. doi:10.1016/j.tranon.2024.101900
3. Dong S, Wang P, Zhang L, et al. The Qi Yin San Liang San decoction enhances anti-CD19 CAR-T cell function in the treatment of B-cell lymphomas. J Ethnopharmacol. 2024;319(Pt 1):117109. doi:10.1016/j.jep.2023.117109
4. Liu Y, Fang Y, Chen X, et al. Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci Immunol. 2020;5(43):eaax7969. doi:10.1126/sciimmunol.aax7969
5. Hunter BD, Jacobson CA. Car T-cell associated neurotoxicity: Mechanisms, clinicopathologic correlates, and future directions. JNCI: Journal of the National Cancer Institute. 2019;111(7):646-654. doi:10.1093/jnci/djz017
6. Zarei M, Abdoli S, Farazmandfar T, Shahbazi M. Lenalidomide improves NKG2D-based CAR-T cell activity against colorectal cancer cells invitro. Heliyon. 2023;9(10):e20460. Published 2023 Sep 27. doi:10.1016/j.heliyon.2023.e20460
7. Yang L-R, Li L, Meng M-Y, et al. IL-7 promotes CD19-directed CAR-T cells proliferation through miRNA-98-5p by targeting CDKN1A. International Immunopharmacology. 2023;124(Part B). doi:10.1016/j.intimp.2023.110974