CELL INTELLIGENCE · 肿瘤细胞治疗研究

TP53 mutations are among the strongest adverse prognostic factors in large B-cell lymphoma (LBCL) treated with chemoimmunotherapy. Whether this unfavorable prognostic impact persists in the era of chimeric antigen receptor (CAR) T-cell therapy remains controversial, largely due to the lack of non-CAR-T comparator cohorts. We aimed to explore whether the adverse prognostic impact of TP53 mutations differs according to treatment modality, particularly in patients receiving CAR-T therapy versus chemotherapy-based approaches.

We retrospectively analyzed 195 adult patients with r/r LBCL who underwent Next-Generation Sequencing (NGS). TP53 mutations were identified in 75 patients (38%). Overall, 151 patients received CD19-directed CAR-T cell therapy, while 44 received non-CAR-T chemotherapy-based treatments. Mutational architecture, including mutation type (missense vs. disruptive) and protein domain (DNA-binding domain [DBD] vs. non-DBD), was also evaluated within the TP53-mutant cohort. Patients were stratified into four groups according to TP53 mutation status and treatment modality. Treatment responses were assessed per Lugano 2014 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared using log-rank tests.

Among TP53 -mutated patients, CAR-T therapy was associated with significantly improved outcomes compared with chemotherapy, with higher objective response rates (56.6% vs 18.2%) and markedly prolonged median OS (12.13 vs 2.20 months; P <.0001). In TP53 wild-type patients, CAR-T therapy also resulted in superior survival compared with chemotherapy (median OS, 25.15 vs 8.28 months; P = .003). Within the CAR-T-treated cohort, TP53 -mutated patients achieved objective and complete response rates comparable to those of TP53 wild-type patients, although median OS and PFS were shorter. The superior efficacy of CAR-T was consistent across different TP53 mutation types, although patients with mutations localized outside the DBD (non-DBD) demonstrated a trend toward further improved survival ( P = 0.046). The incidence and severity of CAR-T-related toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and grade 3 hematologic adverse events, were similar regardless of TP53 mutation status.

Although TP53 mutations are associated with poor prognosis in patients treated with chemotherapy, their adverse prognostic impact appears to be attenuated in the context of CAR-T cell therapy. These findings suggest that CAR-T therapy may partially mitigate the negative impact of TP53 alterations.