Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with signifi cant 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-specifi c 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 fl uid (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 proinfl ammatory CSF cytokines and a pan–T cell encephalitis. SIGNIFICANCE: We provide the fi rst 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 infi ltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinfl ammatory cytokines in the CSF.
Bibliographical noteFunding Information:
C.J. Turtle reports receiving commercial research grants from Juno Therapeutics and Nektar Therapeutics, has ownership interest (including patents) in Precision Biosciences, and is a consultant/advisory board member for Juno Therapeutics, Precision Biosciences, Cel-gene, and Gilead. S. Riddell reports receiving a commercial research grant from Juno Therapeutics, has ownership interest (including patents) in Juno Therapeutics, and is a consultant/advisory board member for Juno Therapeutics, Adaptive Biotechnologies, NOHLA Therapeutics, and Cell Medica. L.S. Kean is a consultant for Kymab Ltd., Bristol-Myers Squibb, Equillium, Calimmune, and Alpine Sciences; reports receiving commercial research grants from Bristol-Myers Squibb and Regeneron, and is a consultant/advisory board member for Jazz. M.C. Jensen reports receiving a commercial research grant from Juno Therapeutics, Inc., and is a consultant/advisory board member for the same. No potential conflicts of interest were disclosed by the other authors.
This work was supported by the NIH (grants P01CA065493, to B.R. Blazar; 1R01HL095791, 2U19AI051731, 1UM1AI126617, U19AI117945, and R33AI116184, to L.S. Kean; and 2R01CA136551, to M.C. Jensen) and the Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Cancer Center Support grant (to M.C. Jensen). A. Taraseviciute was supported by a departmental Ruth L. Kirschstein NRSA training grant (T32CA009351). Additional support to A. Taraseviciute was provided by the St. Baldrick’s Fellowship, ASCO Conquer Cancer Young Investigator Award, and ASBMT New Investigator Award.