Abstract
Simple SummaryFactors impacting the response to CAR T-cell therapies are not fully understood. In this monocentric prospective study, we describe the outcome of 60 patients with relapsed/refractory diffuse large B-cell lymphoma and transformed follicular lymphoma infused with CD19-directed CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel. We obtained a 40% complete metabolic response and a 27% partial metabolic response with a median progression-free survival of 3.1 months and a median of overall survival of 12.3 months. We also found that age-adjusted IPI at the time of infusion, product features, in vivo expansion, and CAR T-cell exhaustion phenotype were significatively associated with the efficacy of the CAR T-cell therapy.CD19-directed CAR T-cells have been remarkably successful in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (t-FL). In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Complete and partial metabolic responses (CMR/PMR) were obtained in 40% and 23% of patients, respectively. After 6.9 months of median follow-up, median progression-free survival (mPFS) and overall survival (mOS) were estimated at 3.1 and 12.3 months, respectively. Statistical analyses revealed that CMR, PFS, and OS were all significantly associated with age-adjusted international prognostic index (aaIPI, p < 0.05). T-cell subset phenotypes in the apheresis product tended to correlate with PFS. Within the final product, increased percentages of both CD4 and CD8 CAR+ effector memory cells (p = 0.02 and 0.01) were significantly associated with CMR. Furthermore, higher CMR/PMR rates were observed in patients with a higher maximal in vivo expansion of CAR T-cells (p = 0.05) and lower expression of the LAG3 and Tim3 markers of exhaustion phenotype (p = 0.01 and p = 0.04). Thus, we find that aaIPI at the time of infusion, phenotype of the CAR T product, in vivo CAR T-cell expansion, and low levels of LAG3/Tim3 are associated with the efficacy of CAR T-cell therapy in DLBCL patients.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most frequent B-cell lymphoma in adults
We evaluated the outcome of R/R diffuse large B-cell lymphoma (DLBCL) patients treated with axi-cel or tisa-cel at the University of Montpellier Hospital as a function of their clinical characteristics, chimeric antigen receptor (CAR) SCT Stem Cell Transplantation (T-cells) product, and CAR T-cell phenotype following infusion
We report the outcome of 60 patients with R/R DLBCL and transformed follicular lymphoma (t-FL) who were consecutively treated with commercial CAR T-cells in a single university center
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most frequent B-cell lymphoma in adults. Tisa-cel, axi-cel, and liso-cel all target the CD19 surface antigen through the FMC63 ScFv and activate the engineered T-cell via intracellular signaling domains, combining a CD3-ζ domain with either a CD28 (axi-cel) or 4-1BB (CD137, tisa-cel, liso-cel) co-stimulatory domain. While these different CARs exhibit potent anti-tumor activity, ex vivo and murine experiments have suggested that the different co-stimulatory domains modulate CAR T expansion and exhaustion [5,6,7,8]
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