Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia

Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2. We used synthetic chimeric antigen receptors(CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia(CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cellsto identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cellsfrom complete-responding patients with CLL were enriched in memory-related genes, including IL-6/ STAT3signatures, whereas T cellsfrom nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO–CD8+ T cellsbefore CAR T cellgeneration, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cellsfrom patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cellexpansion. IL-6/ STAT3blockade diminished CAR T cellproliferation. Furthermore, a mechanistically relevant population of CD27+PD-1–CD8+ CAR T cellsexpressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cellbiology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.