Introduction: Chimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment of relapsed or refractory B-cell malignancies. Repeat CAR T-cell therapy (CART2) is a potential approach for patients with suboptimal response to initial treatment or who relapse. Here we report outcomes with repeat CAR-T (CART2) in such patients.

Methods: Following PRISMA guidelines, a comprehensive search of PubMed, Cochrane, Embase, Google Scholar, and ClinicalTrials.gov (inception to May 2025) was conducted using MeSH terms for “ Repeat CAR-T”, “CART2”, and “Repeat Chimeric Antigen Receptor T-cell therapy.” After screening and excluding review articles, meta-analyses, and studies without a patient population of interest, five studies were selected for inclusion. Statistical analysis was carried out using the meta package in R. The Random effects model was employed for outcomes with high heterogeneity, and the fixed effects model was used when heterogeneity was low. DerSimonian-Laird was used to calculate the inter-study variance. Some characteristics were described systematically.

Results: A total of 133 patients from three retrospective studies, one Phase I study, and one Phase I/II study were included in the analysis. The median age was 38.75 years (range: 7-77), and the majority were males (n = 72/54%). Underlying conditions included acute lymphoblastic leukemia (ALL) (n = 97/73%), non-Hodgkin lymphoma (NHL) (n = 19/14%), and others (n = 17/13%). The majority of patients (n = 123/93) had received anti-CD-19 CAR-T cell therapy before the CART2. The time between CART1 and CART2 ranged from 70 to 373 days. The most common reasons for CART2 included relapse or progression after the initial CAR-T (CART1) (82/62%), and partial or no response (29/22%). CART2 targeted CD19 (n = 113/85%), CD22 (n = 16/12%), and both CD 19/22 (n = 4/3%). The pooled rates for overall response (ORR), complete response, and partial response were 55% (95% CI: 0.31-0.77; I² = 76.8%, p=0.0048), 42% (95% CI: 0.18-0.68; I² = 80.5%, p=0.0015), and 13% (95% CI: 0.05-0.23; I² = 0%, p=0.4450), respectively. The median progression-free survival (PFS) and median overall survival (OS) after CART2 were reported to be 6.2 months and 11.2 months, respectively, in one study. The response rate, mPFS, and mOS were 80.0% (8/10), 7.9 months, and 25.1 months, respectively, in patients who received CART2 after progression from CART1 therapy and consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT). The pooled rate for relapse after CART2 was 82% (95% CI: 0.28-1; I² = 79.8%, p = 0.0262), and the pooled rate of grade 3 or higher adverse events was 2% (95% CI: 0.00-0.10; I² = 0.0%, p = 0.4417).

Conclusion: CART2 showed a suboptimal response compared to CART1, but remains a viable option in patients who progress after CART1, especially those who receive consolidative allo-HSCT after CART1. Prospective trials with larger patient populations are needed to understand the outcomes of CART2 therapy better.

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2025
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