J Transl Med. 2026 Jun 6. doi: 10.1186/s12967-026-08394-6. Online ahead of print.
ABSTRACT
BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy in relapsed/refractory large B-cell lymphoma (R/R LBCL), yet nearly 40-60% of patients fail to achieve durable responses. The mechanisms underlying interpatient variability in CAR-T expansion and persistence remain incompletely understood. In this exploratory study, we preliminarily investigated the associations between baseline peripheral blood immune subsets, CAR-T expansion kinetics, and clinical outcomes.
METHODS: We retrospectively analyzed 33 patients with R/R LBCL who received CD19/CD22 bispecific chimeric antigen receptor T-cell therapy (CAR2219) at our center. Peripheral blood samples were analyzed by flow cytometry. CAR-T cell expansion was monitored longitudinally, and group-based trajectory modeling (GBTM) classified patients into expansion patterns. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analysis and Cox regression. Twenty-two patients received tislelizumab (a PD-1 inhibitor) as maintenance therapy (200 mg intravenously every 3 weeks) starting on day 28 after CAR-T infusion. This regimen was not used as prior therapy, bridging therapy, or co-infusion, rather, it was designed to potentially enhance CAR-T persistence after the initial expansion phase. Given the small sample size (n = 33) and the exploratory nature of the analyses, all findings are hypothesis-generating only and require validation in large prospective cohorts.
RESULTS: Two distinct CAR-T expansion trajectories were identified: a low-expansion group (Group 1, n = 18) and a high-expansion group (Group 2, n = 15). Compared to Group 1, Group 2 exhibited higher peak expansion (Cmax, p < 0.001), greater total exposure (area under the curve (AUC), p < 0.001), and delayed time to peak (Tmax, 14 days vs. 10 days). Group 2 had higher baseline naive T cells (FDR-adjusted p = 0.024), helper T cells (FDR-adjusted p = 0.006), and CD4/CD8 ratio (FDR-adjusted p = 0.049), and fewer activated regulatory T cells (Tregs) (FDR-adjusted p = 0.018). Higher CD4/CD8 ratio associated with longer PFS (HR 0.41, 95% CI 0.17-0.73, p = 0.047). In exploratory subgroup analyses, a directional trend toward longer PFS was noted among patients with high baseline PD-1 expression who received PD-1 inhibitor maintenance therapy, whereas no such trend was observed in those without maintenance. These hypothesis-generating observations require validation in larger prospective cohorts.
CONCLUSION: Baseline immune cell composition may associate with CAR-T expansion and outcomes in R/R LBCL. Exploratory subgroup analyses suggested that the direction of association between baseline PD-1 expression and PFS may differ according to receipt of PD-1 inhibitor maintenance therapy (initiated on day 28 post-infusion), though no statistical significance was reached in either subgroup. Current evidence does not support the clinical use of baseline PD-1 expression as a predictive biomarker, and further validation in prospective studies is warranted.
PMID:42251370 | DOI:10.1186/s12967-026-08394-6
