Dynamics of Immune Reconstitution and Impact on Outcomes across CAR-T Cell Products in Large B-cell Lymphoma

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.

Figure 1.

Immune subset trajectories from the time of CAR-T (time 0) through 1 year (time 365) following CAR-T. Subsets include (A) CD3⁺ T cells, CD3^-19⁺ B cells, and CD3^-56⁺16⁺ NK cells, (B) CD4⁺ T cells and CD8⁺ T cells, (C) CD4⁺ T-cell subsets including CCR7⁺CD45RA⁺ naïve cells, CCR7⁻CD45RA⁺ effector cells, CCR7⁻CD45RA⁻ EM cells, and CCR7⁺CD45RA⁻ CM cells, (D) and CD8⁺ T-cell subsets including CCR7⁺CD45RA⁺ naïve cells, CCR7⁻CD45RA⁺ TEMRA cells, CCR7⁻CD45RA⁻ EM cells, and CCR7⁺CD45RA⁻ CM cells. Trajectories depicted are estimated using locally estimated scatterplot smoothing or local regression modeling. CM, central memory; TEMRA, CD8⁺CCR7^–CD45RA⁺ effector cells.

Figure 2.

Boxplots with superimposed dot plots demonstrate immune subset distributions at clinically significant timepoints, including days 30, 100, 180, and 365 after CAR-T. Axi-cel is shown in blue, liso-cel in green, and tisa-cel in red. Subsets shown are (A) CD3⁺ T cells, (B) CD4⁺ T cells, (C) CD8⁺ T cells, (D) CD4⁺CCR7⁻CD45RA⁻ EM cells, (E) CD3^-19⁺ B cells, and (F) CD3^-56⁺16⁺ NK cells. Ranges of days 20–45, days 80–120, days 150–210, and days 300–400 were used to calculate the distributions for the boxplots for days 30, 100, 180, and 365, respectively. Note the differences in y-axes across panels. Asterisks above each set of bar plots represent P values as calculated by the Kruskal–Wallis test. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 (the absence of any asterisks indicates P > 0.05).

Figure 3.

Kaplan–Meier survival curves for OS and PFS. Comparisons include (A) OS and (B) PFS for CD4⁺ T-cell counts above and below 50 cells/µL and (C) OS and (D) PFS for CD3^-56⁺16⁺ NK cell counts above and below the median day 30 metric of 101 cells/µL. P values are derived from the multivariate Cox proportional hazards model stratified by CAR-T product and adjusted for confounders, including pre–CAR-T age, LDH pre-lymphodepletion, and bridging.