To identify CAR T biomarkers of progressive disease (PD) or toxicity, Good and Spiegel et al. carried out proteomic analysis (CY-TOF) of circulating CAR T cells from 32 patients with large B-cell lymphoma (LBCL) who were treated with CD19-CAR (axi-cel). At 7-day peak CAR T levels, increased numbers of polyclonal (CD4+Helios+FOXP3+) CAR Treg cells with low cytotoxicity correlated with 6-month disease progression and less severe neurotoxicity; similar analysis of a 31-patient cohort validated these results. A model that measured LDH (for tumor burden) combined with CAR Treg numbers better predicted clinical responses.
Contributed by Katherine Turner
ABSTRACT: Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4(+)Helios(+) CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity. Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (T(Reg)) cells. Validation cohort analysis upheld the link between higher CAR T(Reg) cells with clinical progression and less severe neurotoxicity. A model combining expansion of this subset with lactate dehydrogenase levels, as a surrogate for tumor burden, was superior for predicting durable clinical response compared to models relying on each feature alone. These data credential CAR T(Reg) cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and raise the prospect that this subset may regulate CAR T cell responses in humans.
Author Info: (1) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Biomedical Data Science, Stanford University
Author Info: (1) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA. (2) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. (3) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (4) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (5) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (6) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Homer Stryker M.D. School of Medicine, Western Michigan University, Kalamazoo, MI, USA. (7) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (8) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (9) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Cancer Research Lab, Flow Cytometry Core Facility, University of California, Berkeley, Berkeley, CA, USA. (10) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (11) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (12) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (13) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. (14) Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA. (15) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. (16) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Laboratory for Cell and Gene Medicine, Stanford University School of Medicine, Stanford, CA, USA. Syncopation Life Sciences, San Mateo, CA, USA. (17) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Laboratory for Cell and Gene Medicine, Stanford University School of Medicine, Stanford, CA, USA. (18) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. (19) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. Department of Hematology and Hematopoietic Cell Transplantation, Division of Lymphoma, City of Hope National Medical Center, Duarte, CA, USA. (20) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. (21) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. (22) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA. (23) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (24) Stanford Genomics Facility, Stanford University School of Medicine, Stanford, CA, USA. (25) Stanford Genomics Facility, Stanford University School of Medicine, Stanford, CA, USA. (26) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (27) Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA. Department of Statistics, Stanford University, Stanford, CA, USA. (28) Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. (29) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. dmiklos@stanford.edu. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. dmiklos@stanford.edu. (30) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
