American Association for Cancer Research
Browse

Figure S1, Figure S2, Figure S3, Figure S4 from Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia

Download (729.52 kB)
journal contribution
posted on 2023-04-03, 21:41 authored by Bianca D. Santomasso, Jae H. Park, Darin Salloum, Isabelle Riviere, Jessica Flynn, Elena Mead, Elizabeth Halton, Xiuyan Wang, Brigitte Senechal, Terence Purdon, Justin R. Cross, Hui Liu, Behroze Vachha, Xi Chen, Lisa M. DeAngelis, Daniel Li, Yvette Bernal, Mithat Gonen, Hans-Guido Wendel, Michel Sadelain, Renier J. Brentjens

Figure S1: Detailed time course of neurotoxicity for each patient; Figure S2: Serum cytokines in relation to tocilizumab and corticosteroid administration; Figure S3: Hematopoietic toxicity and coagulopathy in severe neurotoxicity; Figure S4: Angiopoietin 1 and 2 alterations in severe neurotoxicity

Funding

NIH

Carson Family Charitable Trust

Emerald Foundation

Mr. and Mrs. Goodwyn Commonwealth Fund

Canada Club of New York

William Laurence and Blanche Hughes Foundation

Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center

Juno Therapeutics

Lake Road Foundation

Memorial Sloan Kettering Cancer Center

Parker Institute for Cancer Immunotherapy

American Society of Clinical Oncology

American Society of Hematology

Leukemia and Lymphoma Society

National Comprehensive Cancer Center

History

ARTICLE ABSTRACT

CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood–cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system–specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.Significance: We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. Cancer Discov; 8(8); 958–71. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899