Chimeric Antigen Receptor T Cell–Mediated Neurotoxicity in Nonhuman Primates

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. 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. .

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

“…The onset of CRES can be biphasic, occurring con currently with CRS and/or after CRS has resolved, and the precise pathophysiology remains unclearalthough evidence implicates a combination of endothe lial activation in the CNS, elevated cytokine levels in the cerebrospinal fluid (CSF), and cerebral T cell infiltra tion 118,119 . The use of anti IL6 therapy seems to be more effective for the management of CRES that occurs con currently with CRS.…”

Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

“…3 CAR-T treatment is frequently complicated by cytokine release syndrome (CRS), 4,5 which manifests with fever, hypotension, and vascular leak. Evidence is emerging that systemic inflammatory signaling during CAR-T cell expansion leads to disruption of the blood-brain barrier (BBB), 8,9 and that monocyte-derived cytokines are required for the development of toxicity. 6 The designation immune effector cell-associated neurotoxicity syndrome (ICANS) was recently proposed by a consensus group of the American Society of Bone Marrow Transplantation 7 to comprise all neurological toxicities that occur with cell-based immunotherapy.…”

Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis

“…172 Using the NHP model, we demonstrated CAR-T-cell expansion and B-cell aplasia, as well as CRS and neurotoxicity that closely mirrors what has been observed clinically. 171 Thus, this model induces elevations in the serum of multiple cytokines, and has documented disproportionately high concentrations of several cytokines in the CSF. Importantly, it has also been able to recapitulate clinical and histopathologic neurotoxicity.…”

“…To address this, my research group, in collaboration with Michael Jensen's laboratory, has recently developed the first nonhuman primate (NHP) model of CRS and neurologic toxicity, using CD20 CAR-T cells in rhesus macaques 171 and Bruce Blazar's group has recently developed a mouse model of CAR-T toxicity, in which human CD19-specific mouse CAR-T cells were adoptively transferred into mice whose normal B cells express a hCD19 transgene at hemizygous levels. 172 Using the NHP model, we demonstrated CAR-T-cell expansion and B-cell aplasia, as well as CRS and neurotoxicity that closely mirrors what has been observed clinically.…”