Clinical, tumor, and product features associated with outcomes after axicabtagene ciloleucel therapy in follicular lymphoma

BACKGROUNDAxicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T cell therapy, demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B cell lymphomas in the ZUMA-5 trial.METHODSHere, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 patients with follicular lymphoma (FL).RESULTSIn univariate and multivariate analyses, pretreatment inflammatory markers, including TNF-α and IL-12p40, as well as total metabolic tumor volume (TMTV), associated with disease progression. Conversely, T-naive-like product phenotype associated with improved outcome, particularly in patients with high TMTV. These covariates improved risk stratification when combined with the FL International Prognostic Index. Postinfusion, CAR T cell expansion associated with improved outcome, while serum inflammatory and immunomodulatory markers, including TNF-α, associated with disease progression and occurrence of high-grade cytokine release syndrome or neurologic events, presenting targets to improve the therapeutic index of axi-cel in FL. Tumor gene expression profiling revealed that both type I and II IFN signaling associated with disease progression and higher expression of T cell exhaustion markers, including TIM3 and LAG3. Pre- or posttreatment CD19 expression on tumor was not associated with outcome.CONCLUSIONThese findings offer insights into mechanisms of resistance and toxicity, risk stratification, and strategies for development of next generation CAR-T approaches.TRIAL REGISTRATIONClinicalTrials.gov NCT03105336.FUNDINGKite, a Gilead Company.