CAR-T cell therapy in TP53-mutated CNS lymphoma: overcoming a high-risk genetic barrier

Background Central nervous system lymphoma (CNSL) is a rare but aggressive subtype of lymphoma that presents significant therapeutic challenges. The prognosis for patients with CNSL varies significantly based on several genetic factors, including TP53 mutations, which are among the most critical determinants of treatment outcomes. Chimeric antigen receptor T (CAR-T) cell therapy has shown promising results in several hematological malignancies, including B-cell lymphomas. However, its efficacy in CNSL, particularly in patients with TP53 mutations, requires further investigation. Methods A retrospective cohort study was conducted on 61 CNSL patients who had been treated at our institution from 2020 to 2024. The median follow-up time was 14.5 months. A total of 43 patients received CAR-T cell infusion therapy. The overall survival (OS) and progression-free survival (PFS) of patients harboring TP53 mutations (TP53+) and those with wild-type TP53 (TP53−) were compared. In addition, factors associated with patient prognosis were also identified. Results Among the 43 patients who received CAR-T cell therapy, 17 harbored TP53 mutations. The median age of the cohort was 51.5 years, and 51.2% of the patients (22/43) were male. The overall response rate (ORR) and the complete response rate (CRR) in the TP53+ CAR-T+ group were both 64.5% (11/17), the median OS duration was 14.07 months (95% CI 12.63–∞), and the median PFS duration was 12.77 months (95% CI 6.33–∞). In the TP53-CAR-T+ group, the ORR was 73.3% (19/26), the CRR was 69.2% (18/26), the median OS duration was 33.47 months (95% CI 11.23–∞), and the median PFS duration was 22.4 months (95% CI 6.13–∞). In the subgroup analysis, the cell-of-origin (COO) classification was a key factor influencing the long-term survival of CSNL patients; in the TP53+ group, patients with non-germinal center B-cell-like (GCB) classification had longer OS compared to the GCB subtype ( p = 0.003). Conclusion CAR-T cell therapy is an effective treatment for CNSL patients harboring TP53 mutations and has the same efficacy as traditional treatment methods. Additionally, CAR-T cells may be more effective for TP53+ CSNL patients with a non-GCB classification.