Data from Chimeric Antigen Receptor T Cell–Mediated Neurotoxicity in Nonhuman Primates
Year: 2023
Type: other
Abstract: Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell–mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell–mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan–T cell encephalitis. Significance: We provide the first immunologically relevant, nonhuman primate model of B cell–directed CAR T-cell therapy–mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750–63. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663
Authors: Agne Taraseviciute, Victor Tkachev, Rafael Ponce, Cameron J. Turtle, Jessica M. Snyder, H. Denny Liggitt, David Myerson, Luis Gonzalez-Cuyar, Audrey Baldessari, Chris English, Alison Yu, Hengqi Zheng, Scott N. Furlan, Daniel J. Hunt, Virginia Hoglund, Olivia Finney, Hannah Brakke, Bruce R. Blazar, Carolina Berger, Stanley R. Riddell, Rebecca Gardner, Leslie S. Kean, Michael C. Jensen
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4392721657