Using a CRISPR/Cas9-based, genome-wide loss-of-function screen, Singh and Lee et al. showed that impaired apoptotic death receptor signaling (e.g. FADD, BID) in acute lymphoblastic leukemia (ALL) cells led to persistence of ALL cells, prolonged exposure to antigen, and ultimately, transcriptional and epigenetic reprogramming of CAR T cells that was indicative of, but not identical to, classic dysfunction. In patients with ALL treated with tisagenlecleucel (CART19), lower expression of a death receptor gene signature correlated with reduced CART19 expansion, lack of response, and strikingly lower overall survival.
Contributed by Anna Scherer
Primary resistance to CD19-directed chimeric antigen receptor T cell therapy (CART19) occurs in 10-20% of patients with acute lymphoblastic leukemia (ALL), however the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T cell cytotoxicity which permitted antigen persistence and was subsequently magnified by the induction of CAR T cell functional impairment. These findings were validated using samples from two CAR T cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T cell failure by impairing T cell cytotoxicity and promoting progressive CAR T cell dysfunction.
Author Info: (1) University of Pennsylvania nathan.singh@wustl.edu. (2) University of Pennsylvania. (3) University of Pennsylvania. (4) Center for cellular Immunotherapies, University of Pennsy
Author Info: (1) University of Pennsylvania nathan.singh@wustl.edu. (2) University of Pennsylvania. (3) University of Pennsylvania. (4) Center for cellular Immunotherapies, University of Pennsylvania. (5) Biomedical and Health Informatics, Children's Hospital of Philadelphia. (6) University of Pennsylvania. (7) University of Pennsylvania. (8) Center for Cellular Immunotherapies (CCI), University of Pennsylvania. (9) Center for cellular immunotherapies, University of Pennsylvania. (10) Center for Cellular Immunotherapies, University of Pennsylvania. (11) Novartis. (12) PK Sciences, Novartis Institutes for BioMedical Research. (13) University of Pennsylvania. (14) (15) Children's Hospital of Philadelphia. (16) Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia. (17) University of Pennsylvania. (18) Division of Oncology, Children's Hospital of Philadelphia. (19) Division of Oncology, Children's Hospital of Philadelphia. (20) Parker Institute for Cancer Immunotherapy, University of Pennsylvania. (21) Division of Hematology-Oncology and Center for Cellular Immunotherapies, University of Pennsylvania. (22) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania.
