CAR-t cell therapy in TP53-mutated CNS lymphoma: Overcoming a high-risk genetic barrier

Abstract 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, with TP53 mutations being one of the most critical determinants of treatment outcomes. Previous studies have highlighted the poor prognosis associated with TP53 mutations in various cancers, including lymphoma, but the impact on CNSL remains underexplored. Chimeric antigen receptor T-cell (CAR-T) therapy has shown promising results in several hematological malignancies, including B-cell lymphomas, yet its efficacy in CNSL, particularly in patients with TP53 mutations, requires further investigation. Objectives: To evaluate the efficacy and safty of CAR-T therapy in CNSL patients with TP53 mutations, and clarify the accessibility of CAR-T therapy for patients with TP53-mutated central lymphoma. Methods A retrospective cohort study was conducted, including 61 CNSL patients treated at our institution from 2020 to 2024. The median follow-up time was 14.5 months. All 61 patients were divided into four groups: patients with TP53 mutations with (TP53+CAR-T+, n=17) or without CAR-T therapy (TP53+CAR-T-, n=4), and patients without TP53 mutations with (TP53-CAR-T+, n=26) or without CAR-T therapy (TP53-CAR-T-, n=14). The endpoint were overall response rate (ORR), complete response rate (CRR), overall survival (OS), progression-free survival (PFS) and adverse event profiles. The efficacy assessment follows the Lugano 2014 criteria. Subgroup analyses were performed to assess the effects of TP53 mutation status on clinical outcomes. Statistical analyses were performed using Kaplan-Meier survival curves, log-rank tests, and multivariate Cox regression models to adjust for potential confounders. Results: Of the 61 CNSL patients included, 21 had TP53 mutations. The median age is 54 years old. TP53+CAR-T+ group patients overall response rate (ORR) is 11/17 (64.5%). and complete response rate(CRR) is 11/17 (64.5%). TP53+CAR-T- group patients ORR is 3/4 (75%). and CRR is 3/4 (75%). TP53-CAR-T+ group patients ORR is 19/26 (73.3%). and CRR is 18/26 (69.2%). TP53-CAR-T- group patients ORR is 9/14 (64.3%). and CRR is 8/14 (57.1%).The median PFS for patients treated with CAR-T therapy was longer in the TP53- group compared to the TP53+ group, with a median PFS of 20.17 months versus 24.07 months. The median OS for TP53+CAR-T+ group patients was not reach, and TP53-CAR-T+ group patients was 27.87 months. The median PFS for patients with TP53 mutation was similar in CAR-T treatment group and non-CAR-T treatment group, with a median PSF of 20.17 months versus 18.9 months. However, there was no statistical significance. Nevertheless, we can still draw the conclusion that CAR-T has a significant therapeutic effect on central nervous system lymphoma with TP53 mutations. In the subgroup analysis, we found that COO was a key factor influencing the long-term survival of patients with central lymphoma. Further, through Kaplan-Meier survival and log-rank tests, it was discovered that compared to the TP53- group, the overall survival time of non-GCB subtype patients in the TP53+ group was longer (p = 0.003). Adverse event profiles were comparable between the TP53+CAR-T+ group and TP53+CAR-T- group, with no significant increase in toxicity related to TP53 mutations. Interestingly, patients with TP53 mutations exhibited lower overall survival after conventional therapies (chemotherapy, stem cell transplant) when compared to those without TP53 mutations, suggesting that the mutation may confer resistance to standard treatments. Conclusion: Our study indicated that CAR-T therapy is an effective treatment for CNSL with TP53 mutations, and it has the same efficacy as traditional treatment methods or those without TP53 mutations. However, due to the lack of significant efficacy in patients with TP53 mutations, it suggests the necessity of adopting alternative or combined therapies. Subgroup analysis shows that when choosing the most appropriate treatment plan for CNSL, in addition to considering the TP53 mutation status, the COO classification should also be taken into account. For patients with TP53 mutations and non-GCB classification, CAR-T therapy may have better efficacy.