Dynamics of Immune Reconstitution and Impact on Outcomes across CAR-T Cell Products in Large B-cell Lymphoma
Danny Luan, Susan DeWolf, Teng Fei, Sandeep Raj, Gunjan L. Shah, Caleb A. Lareau, Mohammad Alhomoud, Gilles Salles, Alfredo Rivas‐Delgado, Kai Rejeski, Jae H. Park, Efrat Luttwak, Alejandro Luna, Magdalena Corona, Evangelos Ntrivalas, Giulio Cassanello, Marina Gomez-Llobell, Allison Parascondola, Michael Scordo, Katharine C. Hsu, M. Lia Palomba, Miguel‐Angel Perales, Roni Shouval
Abstract
ABSTRACT: Patients treated with chimeric antigen receptor T-cell (CAR-T) therapy are subject to profound immunosuppression. Dynamics of immune reconstitution (IR) and impacts of IR on outcomes following infusion across CAR-T products are not well understood. In this study, we profiled IR in 263 patients with relapsed/refractory large B-cell lymphoma receiving CAR-T therapy (axicabtagene ciloleucel 44.9%, lisocabtagene maraleucel 30.4%, and tisagenlecleucel 24.7%). Following infusion, patients remain persistently immunosuppressed, with 48.1% having CD4+ T-cell counts <200/µL and the median CD3-CD19+ B-cell counts remaining zero through 1 year after CAR-T therapy. IR differences exist by product, with the fastest CD4+ T-cell recovery seen for tisagenlecleucel, driven primarily by more rapid recovery of the CD4+CCR7−CD45RA− effector memory subset. NK cell, but not CD4+ T cell, recovery is significantly associated with favorable progression-free (HR, 0.65; 95% confidence interval, 0.48–0.88) and overall survival (HR, 0.64; 95% confidence interval, 0.44–0.92) and inversely correlated with inflammatory markers measured at the time of infusion. SIGNIFICANCE: This study reveals differences in IR patterns after CAR-T therapy in patients with large B-cell lymphoma, with early NK cell recovery emerging as a key predictor of survival. These findings provide potential future avenues of research for improving patient outcomes and tailoring post-therapy management strategies to mitigate relapse risk.