Development of molecular and pharmacological switches for chimeric antigen receptor T cells
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The use of chimeric antigen receptor (CAR) T cell technology as a therapeutic strategy for the treatment blood-born human cancers has delivered outstanding clinical efficacy. However, this treatment modality can also be associated with serious adverse events in the form of cytokine release syndrome. While several avenues are being pursued to limit the off-target effects, it is critically important that any intervention strategy has minimal consequences on long term efficacy. A recent study published in Science Translational Medicine by Dr. Hudecek’s group proved that dasatinib, a tyrosine kinase inhibitor, can serve as an on/off switch for CD19-CAR-T cells in preclinical models by limiting toxicities while maintaining therapeutic efficacy. In this editorial, we discuss the recent strategies for generating safer CAR-T cells, and also important questions surrounding the use of dasatinib for emergency intervention of CAR-T cell mediated cytokine release syndrome.
The validation of chimeric antigen receptor (CAR) T cell technology as a viable, therapeutic strategy for the treatment of blood-born human cancers has resulted in a renewed focus on ways to optimize and control this treatment modality [1, 2]. CAR constructs are generated by linking an extracellular antibody-antigen recognition fragment with a costimulatory and intracellular activation domain from the T cell receptor complex, allowing for T cell recognition and clearance of tumors. The FDA has recently approved two CD19-directed CAR-T cell programs, Tisagenlecleucel (Kymriah) and Axicabtagene ciloleucel (Yescarta), for the treatment of various B cell malignancies including diffuse large B cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). As is the case with other cancer treatments, CD19-CAR-T cell therapy can also demonstrate serious, adverse side effects, the most common of which being cytokine release syndrome (CRS). CRS is characterized by massive and rapid releases of cytokines into the bloodstream, resulting in morbidity and even mortality in some patients. Different from other traditional cancer drugs, however, CAR-T cells are considered “living drugs” which may reside in patients for years, thereby increasing the probability for undesirable effects. Thus, development of precise techniques to manage the balance of activity and toxicity of CAR-T cells is of extreme importance.
Strategies for safer CAR-T therapy
Combinational targeted activation
Two antigen recognitions are required to fully activate CAR-T cells 
Inhibitory CAR-T cells
Recognition of normal cell induces inhibition of CAR-T cell activity 
Modification of CAR molecules to identify constructs with less cytokine production activity but with preserved anti-tumor function 
On/off switch for CAR-T cell
Dasatinib serves as an on/off switch for CAR-T cells 
As mentioned above, dasatinib is a tyrosine-kinase inhibitor which has been highly effective in treating patients with imatinib-resistant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive ALL. However, as a nonspecific inhibitor, dasatinib has also been shown to interfere with other kinase family’s function such as Src, Btk, and cKit to name a few . Given the exciting work from Mestermann et al., several questions should be investigated prior to adopting the clinical use of dasatinib for controlling CAR-T cell toxicity. First, understanding how dasatinib influences CAR-T cell function in an immune competent setting should be examined. Current standard of care for CAR-T therapy requires a lymphodepletion regimen allowing for enhanced donor T cell engraftment. Considering the complexity of immune reconstitution in this setting, it would be worthwhile to investigate the effects of dasatinib on this process. Secondly, how dasatinib treatment affects the endogenous tumor-specific T cell response should be addressed. The authors showed dasatinib had similar inhibitory effects when stimulating with an endogenous TCR-peptide combination in addition to stimulation with CD19, validating the broad inhibitory properties of the treatment. However, it is unclear if CAR-T cells are more sensitive to dasatinib compared to endogenous T cells due to increased antigen affinity as well as unique configuration of signaling cassette. Finally, it will be interesting to determine if other tyrosine kinase inhibitors have superior effects in inhibiting CAR-T cell mediated CRS by acting as a functional on/off switch.
The current paper from Dr. Hudecek’s group proved that the tyrosine kinase inhibitor dasatinib can serve as an on/off switch for CD19-CAR-T cells in the preclinical models . Clinical studies with dasatinib for the treatment of CRS induced by CAR-T therapy should be approached with caution until more can be elucidated surrounding the potential for off target effects. Nonetheless, the work presented by Mestermann and colleagues offers an enticing approach for reducing toxicity while maintaining efficacy of CAR-T cell therapy.
BXW, NS, BPR and ZL contribute to writing the manuscript. All authors read and approved the final manuscript.
This work is supported by NIH Grants P01CA186866.
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The authors declare that they have no competing interest.
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