Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies.
Katia BeiderOrit ItzhakiJacob SchachterAnia Hava Grushchenko-PolaqValeria Voevoda-DimenshteinEvgenia RosenbergOlga OstrovskyOlivia DevillersRonnie Shapira FrommerLi-At ZeltzerAmos TorenElad JacobyAvichai ShimoniAbraham AvigdorArnon NaglerMichal J BesserPublished in: Cells (2022)
Despite the high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, its full capacity is currently limited by the generation of dysfunctional CAR T cells. Senescent or exhausted CAR T cells possess poor targeting and effector functions, as well as impaired cell proliferation and persistence in vivo. Strategies to detect, prevent or reverse T cell exhaustion are therefore required in order to enhance the effectiveness of CAR T immunotherapy. Here we report that CD19 CAR T cells from non-responding patients with B cell malignancies show enrichment of CD8 + cells with exhausted/senescent phenotype and display a distinct transcriptional signature with dysregulation of genes associated with terminal exhaustion. Furthermore, CAR T cells from non-responding patients exhibit reduced proliferative capacity and decreased IL-2 production in vitro, indicating functional impairment. Overall, our work reveals potential mediators of resistance, paving the way to studies that will enhance the efficacy and durability of CAR T therapy in B cell malignancies.
Keyphrases
- cell therapy
- cell proliferation
- end stage renal disease
- stem cells
- mesenchymal stem cells
- ejection fraction
- newly diagnosed
- induced apoptosis
- randomized controlled trial
- prognostic factors
- single cell
- regulatory t cells
- gene expression
- cell cycle
- dendritic cells
- peritoneal dialysis
- immune response
- risk assessment
- single molecule
- oxidative stress
- signaling pathway
- rheumatoid arthritis
- ulcerative colitis
- drug delivery
- case control
- patient reported