Hsi-Min Chan

Background: Chimeric antigen receptor T (CAR T) cell therapy is a form of cancer immunotherapy where a patient’s T cells are genetically modified to recognize tumor antigens and eliminate cancer cells.^1-3 It utilizes the body’s own defense system to eliminate the cancer, and can reduce the risk of relapse by developing ‘memory’ of the cancer.^3-4 One of the major drawbacks of CAR T cell therapy is the fatal toxicities caused by the sudden increase in T cell receptor engagement and T cell activation.¹ Cytokine release syndrome (CRS) is a common and severe side effect of CAR T cell therapy, which can lead to fever, hypotension and respiratory insufficiency. Aggressive and complicated treatment using anti-cytokine antibodies and receptor antagonists is required to prevent death.⁵ Preventing CAR T cell associated toxicities and ensuring patient safety is one of the first steps to take before CAR T cell applications can be expanded meaningfully.

Objective: Reviewing different methods of engineering CAR T cells to prevent CRS while still maintaining therapeutic efficacy.

Research methods: A literature search of papers relating to ‘CAR T switch’ published between 2018 to 2024 was conducted. Publications that demonstrated controllability of CAR T activation and CRS suppression were further reviewed.

Results: CRS severity is mediated by CAR T cell recruited macrophages, which produce IL-6, IL-1 and nitric oxide. Blocking the actions of IL-1 and IL-6 using antibodies and receptor antagonists are common clinical interventions for CRS. Giavridis et al. further demonstrates that expressing IL-1 receptor antagonists on CAR T cells protects against CRS while maintaining its antitumor activity.⁵ CARs are modelled after T cell receptors and share similar signaling cascades that can be inhibited by tyrosine kinase inhibitors. Dasatinib, a tyrosine kinase inhibitor, provided complete, reversible, and immediate control over CAR T cell activation. It can be co-administered with CAR T cells to partially inhibit CAR T cell and prevent CAR T cell over-activation, or emergency administered to stop CRS.⁶ CAR can also be engineered to create dual antigen MTX-conditional CAR. In the presence of MTX, a standard chemotherapy agent, the CAR is transiently and partially inhibited.⁷ CARs can also be created with ON and OFF switches, in a variety of designs. ON switches require drug administration for CAR activation, and CARs with OFF switches degrade or become inhibited in the presence of the drug.^{8, 9} Thalidomide analogs act as molecular glues between proteins and cereblon, and can be utilized for drug-dependent CAR degradation by recruiting E3 ubiquitin ligase, and dimerization of CAR signalling and recognition domains.⁸ Versatile protease regulatable (VIPER) CARs have been created using the proteolytic activity of Hepatitis C virus NS3 and controlled by NS3 protease inhibitors. VIPER CARs can also be combined with multiple systems to fine tune CAR function.⁹

Conclusions: Thoughtful CAR and CAR T cell design can prevent and reduce risk of CRS.^5-9 All drug inducible CARs provide dose dependent, transient and reversible control of CAR T cell activation.^6-9 However, CAR design is limited by the lentiviral payload used to transduce CAR expression in T cells: complex CARs complicate manufacturing.^6-8 Using chemotherapeutic drugs to modulate CAR T cells is helpful in providing a two-pronged approach to cancer therapy and to facilitate the clinical translation of CAR T cell therapy research.^{6, 7} OFF CARs are more effective in controlling CAR T cell activation and preventing CRS than ON CARs.^{8, 9}

Works Cited:

1. Sterner RC, Sterner RM. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer Journal. 2021;11(4). doi:10.1038/s41408-021-00459-7
2. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359(6382):1361-1365. doi:10.1126/science.aar6711
3. Tan S, Li D, Zhu X. Cancer immunotherapy: Pros, cons and beyond. Biomedicine & Pharmacotherapy. 2020;124:109821. doi:10.1016/j.biopha.2020.109821
4. Hegde PS, Chen DS. Top 10 challenges in cancer immunotherapy. Immunity. 2020;52(1):17-35. doi:10.1016/j.immuni.2019.12.011
5. Giavridis T, van der Stegen SJ, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nature Medicine. 2018;24(6):731-738. doi:10.1038/s41591-018-0041-7
6. Mestermann K, Giavridis T, Weber J, et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med. 2019;11(499):eaau5907. doi:10.1126/scitranslmed.aau5907
7. Park S, Pascua E, Lindquist KC, et al. Direct control of CAR T cells through small molecule-regulated antibodies. Nature Communications. 2021;12(1). doi:10.1038/s41467-020-20671-6
8. Jan M, Scarfò I, Larson RC, et al. Reversible ON- and OFF-switch chimeric antigen receptors controlled by Lenalidomide. Science Translational Medicine. 2021;13(575). doi:10.1126/scitranslmed.abb6295
9. Li H-S, Wong NM, Tague E, Ngo JT, Khalil AS, Wong WW. High-performance multiplex drug-gated CAR circuits. Cancer Cell. 2022;40(11). doi:10.1016/j.ccell.2022.08.0