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A monthly roundup of key articles in other journals

Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy. Good Z, Spiegel JY, Sahaf B, et al., Nat Med. 2022; 28(9):1860–1871 A preponderance of CD4+ Helios+ TReg cells in large B cell lymphoma patients 7 days post-CAR T cell infusion predicts disease progression and less severe neurotoxicity. Following autologous CAR T cell treatment, a substantial proportion of patients with B cell acute lymphoblastic leukemia and large B cell lymphoma (LBCL) are refractory or relapse, but biomarkers for predicting response are limited. Here, Good et al. used highdimensional single-cell proteomic profiling to characterize circulating CAR T cell subsets that could identify patients at risk for disease progression or neurotoxicity following infusion with CD19 CAR T cells. In a discovery cohort of 32 patients with LBCL, median CAR T cell expansion peaked on day 7 after treatment with axicabtagene ciloleucel, and at no timepoint was expansion associated with clinical response or neurotoxicity. Mass cytometry and high throughput proteomics identified circulating CAR T cell populations on day 7 post-infusion that were associated with disease control, progression or severe neurotoxicity: two clusters predicted complete response at 6 months (CD4+ and CD8+ CD57+ T-bet+ CAR T cells), and one T cell population was associated with progressive disease and a lower risk of severe neurotoxicity (CD4+ Helios+ cells). The findings were confirmed in a validation cohort of 31 additional patients. Importantly, the proportions of these cell types were not different between groups prior to infusion of axicabtagene ciloleucel. CD4+ Helios+ cells were for the most part clonally unique with hallmark features of TReg cells, including expression of FOXP3 and CD25. Both the CD4+ and CD8+ CD57+ T-bet+ CAR T cells were clonally expanded populations expressing cytotoxic proteins (Granzyme B) and markers of degranulation (CD107a), respectively. Lactate dehydrogenase (LDH) levels are known to correlate with cancer progression and have been used as a surrogate for tumor burden. Here, LDH and CD4+ Helios+ CAR T cells independently predicted complete response or disease progression, with no significant correlation detected between the two measures. Combining the two independent predictors into a logistic regression model achieved excellent performance in identifying durable complete response both in the discovery and validation cohorts. In sum, post-infusion CAR T cell populations can be used as biomarkers for treatment response: a higher proportion of CD4+ Helios+ cells with a TReg phenotype in circulation following treatment with axicabtagene ciloleucel is associated with clinical disease progression and more mild neurotoxicity, while higher levels of CD57 + T-bet cells possessing a terminal effector T cell phenotype is associated with improved disease control. ♦ ♦ ♦