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Perspective

The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities

1
Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 5052, Australia
2
Department of Medical Biology, The University of Melbourne, Parkville 3052, Australia
*
Authors to whom correspondence should be addressed.
Cancers 2021, 13(1), 38; https://doi.org/10.3390/cancers13010038
Received: 30 November 2020 / Revised: 20 December 2020 / Accepted: 22 December 2020 / Published: 25 December 2020
(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)
The development and refinement chimeric antigen receptor (CAR)-T cell immunotherapy has significantly improved the prognosis of patients with B cell malignancies. Severe treatment related toxicities however remain a significant challenge for the field. This perspective reviews 17 clinical trials of the most widely used anti-CD19 (FMC63) CAR-T cell therapies, with the aim of dissecting the contribution of the structural and costimulatory domains of the CAR to clinical outcomes and toxicities. The CD28 structural hinge and transmembrane CAR domains are highlighted as strongly associated with both clinical efficacy and severe toxicity. This perspective supports further investigation into the structural CAR domains for improved CAR design and safer CAR-T cell therapies.
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B cell malignancies, improving patient survival and long-term remission. Nonetheless, over 50% of patients experience severe treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity. Differences in severity of toxic side-effects among anti-CD19 CARs suggest that the choice of costimulatory domain makes a significant contribution to toxicity, but comparisons are complicated by additional differences in the hinge and transmembrane (TM) domains of the most commonly used CARs in the clinic, segments that have long been considered to perform purely structural roles. In this perspective, we examine clinical and preclinical data for anti-CD19 CARs with identical antigen-binding (FMC63) and signalling (CD3ζ) domains to unravel the contributions of different hinge-TM and costimulatory domains. Analysis of clinical trials highlights an association of the CD28 hinge-TM with higher incidence of CRS and neurotoxicity than the corresponding sequences from CD8, regardless of whether the CD28 or the 4-1BB costimulatory domain is used. The few preclinical studies that have systematically varied these domains similarly support a strong and independent role for the CD28 hinge-TM sequence in high cytokine production. These observations highlight the value that a comprehensive and systematic interrogation of each of these structural domains could provide toward developing fundamental principles for rational design of safer CAR-T cell therapies. View Full-Text
Keywords: CAR-T cell therapy; CD19; clinical trials; CRS; toxicity CAR-T cell therapy; CD19; clinical trials; CRS; toxicity
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MDPI and ACS Style

Davey, A.S.; Call, M.E.; Call, M.J. The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities. Cancers 2021, 13, 38. https://doi.org/10.3390/cancers13010038

AMA Style

Davey AS, Call ME, Call MJ. The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities. Cancers. 2021; 13(1):38. https://doi.org/10.3390/cancers13010038

Chicago/Turabian Style

Davey, Ashleigh S., Matthew E. Call, and Melissa J. Call 2021. "The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities" Cancers 13, no. 1: 38. https://doi.org/10.3390/cancers13010038

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