Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. Higher baseline and postinfusion levels of serum inflammatory markers associated with differentiated/effector products, reduced efficacy, and increased CRS and neurologic events, thus suggesting targets for intervention. These data support better outcomes with earlier CAR T-cell intervention and may improve patient care by informing on predictive biomarkers and development of next-generation products.

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Supplementary data

Supplementary Figures S1-S16

Supplementary Fig. 1. Duration of response did not associate with CAR T-cell peak expansion. Supplementary Fig. 2. CAR T-cell peak did not associate with ongoing response in secondline LBCL. Supplementary Fig. 3. Early CAR T-cell expansion correlated with ongoing response. Supplementary Fig. 4. Naive T cells associated with improved outcome. . Supplementary Fig. 5. Association between toxicity and central memory T-cell product phenotype. Supplementary Fig. 6. Association of product T-cell phenotypes/subpopulations with CAR Tcell expansion. Supplementary Fig. 7. Naive enriched CAR T-cell product was more efficacious in vitro against tumor cells. Supplementary Fig. 8. Select serum inflammatory and immune-modulatory analytes correlated with reduced efficacy and elevated toxicity at baseline and on day 0. Supplementary Fig. 9. Association of T-cell subsets with posttreatment inflammatory serum analytes. Supplementary Fig. 10. Elevated inflammatory profile at baseline differentially correlated with product phenotype. Supplementary Fig. 11. Naive T-cell phenotype associated with higher peak level of VEGF. Supplementary Fig. 12. Coculture IFN-γ associated with toxicity and T-cell phenotype. Supplementary Fig. 13. Coculture IFN-γ association with toxicity and overall best response (CR versus others) by patient. Supplementary Fig. 14. Association of apheresis CD27+CD28+CD8+ naive T cells with response. Supplementary Fig. 15. T naive phenotype in second-line versus third-line LBCL. Supplementary Fig. 16. Gating strategy for CD27 and CD28 costimulatory markers.

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