Frontiers in Immunology | Prof. Kai Hu’s Team: CAR-T Cell Therapy May Mitigate the Adverse Impact of TP53 Mutations in Large B-Cell Lymphoma (LBCL)

Summary: Prof. Kai Hu’s team at Beijing GoBroad Hospital published a retrospective study in Frontiers in Immunology analyzing 195 patients with relapsed/refractory large B-cell lymphoma. The study found that, among patients with TP53 mutations, CAR-T cell therapy was associated with significantly better outcomes than chemotherapy-based treatment, including a higher objective response rate and longer overall survival. The researchers also explored how the location of TP53 mutations may affect prognosis, offering new insights into more precise treatment strategies in the CAR-T era.

TP53 mutations have long been considered one of the most important adverse molecular prognostic markers in large B-cell lymphoma (LBCL) and have been strongly associated with poorer survival outcomes in the chemoimmunotherapy era. Whether this unfavorable prognostic effect persists in the era of CAR-T cell therapy, however, remains controversial, particularly because direct comparisons with non-CAR-T treatment cohorts have been limited.

Recently, Rui Liu from Prof. Kai Hu’s team in the Department of Lymphoma and Myeloma at Beijing GoBroad Hospital published a paper in Frontiers in Immunology titled “Impact of TP53 mutations on survival outcomes in the CAR-T era of large B-cell lymphoma.” The study provides new insights into the use of CAR-T cell therapy for relapsed/refractory LBCL with TP53 mutations.

Research Background

Prof. Kai Hu explained: “To better understand how TP53 mutations affect outcomes with CAR-T therapy in relapsed/refractory large B-cell lymphoma (LBCL), our center retrospectively analyzed 195 patients with R/R LBCL who underwent next-generation sequencing (NGS). Among them, 151 received CD19-directed CAR-T cell therapy and 44 received chemotherapy-based non-CAR-T treatment. Patients were divided into four groups according to TP53 status and treatment modality. We also performed subgroup analyses based on TP53 mutation type—missense versus disruptive mutations—and the protein domain in which the mutation occurred.”

Study Results

1. Clinical Outcomes With Different Treatment Approaches

The study compared CAR-T therapy with conventional chemotherapy-based treatment across different TP53 mutation groups:

For patients with TP53 mutations:

• Objective response rate (ORR): Significantly higher with CAR-T therapy (56.6% vs. 18.2%).

• Overall survival (OS): Median OS was 12.13 months in the CAR-T group, compared with only 2.20 months in the chemotherapy group (P<0.0001).

For patients with TP53 wild-type disease, CAR-T therapy also outperformed chemotherapy, with median OS of 25.15 months versus 8.28 months, respectively (P=0.0030) (Fig. 2A).

2. CAR-T Outcomes According to TP53 Status

Among the 151 patients who received CAR-T therapy:

Similar response rates: The TP53-mutated and TP53 wild-type groups had comparable ORRs (56.6% vs. 45.9%) and complete response rates (CRR; 39.6% vs. 35.7%).

Differences in survival: Despite similar response rates, median OS (12.13 months) and median progression-free survival (PFS; 6.87 months) were shorter in the TP53-mutated group than in the wild-type group (OS, 25.15 months; PFS, 8.98 months).

3. Genomic Landscape and the Impact of Mutation Location

Mutation profile: TP53 was the most frequently mutated gene in the cohort (38.7%), followed by KMT2D (30.9%) and PIM1 (22.7%).

Why the mutation domain matters:

• DNA-binding domain (DBD) mutations: 89% of TP53 mutations occurred in the DBD, and patients with these mutations had poorer outcomes.

• Non-DBD mutations: Patients with TP53 mutations outside the DNA-binding domain had significantly better OS than those with DBD mutations (median OS: not reached vs. 9.86 months; P=0.046).

• Mutation type: No significant survival difference was observed between missense and disruptive mutations, such as truncating mutations.

Histologic interaction: Among patients with TP53 mutations, those with high-grade B-cell lymphoma (HGBL) and double-/triple-hit features showed a trend toward poorer survival.

Summary and Outlook

Prof. Kai Hu noted that the Department of Lymphoma and Myeloma at Beijing GoBroad Hospital has accumulated extensive experience with CAR-T therapy in recent years. As the number of real-world CAR-T cases continues to grow, the clinical challenges are becoming increasingly complex. In clinical practice, patients with TP53 mutations are often highly resistant to chemotherapy, while CAR-T therapy can provide meaningful benefit for some of these patients. Going forward, important priorities in hematologic oncology include choosing the right timing for CAR-T therapy and developing more individualized, precise, and longitudinal management strategies. By integrating clinical, pathologic, molecular, and imaging data, clinicians may be able to identify earlier which patients with relapsed/refractory central nervous system lymphoma (R/R CNSL) who do not respond to conventional treatment could benefit from precision CAR-T approaches. Monitoring tools such as circulating tumor DNA (ctDNA) may also help detect signs of relapse earlier, allowing earlier intervention and potentially extending survival.