Impact of CD58 Mutations on CAR-T Cell Therapy in B-Cell Non-Hodgkin Lymphoma: Clinical Insights and Therapeutic Potential
Authors: Wei Bian , Liu Rui , Yang Fan , Ma Lixia , Guo Yuelu , Zheng Qinlong , Deng Biping , Fu Zhonghua , Ke Xiaoyan , Hu Kai 
Published: December 2024

Background:

CAR-T cell therapy, as a novel treatment for refractory or relapsed B-cell non-Hodgkin lymphoma (B-NHL), has demonstrated significant therapeutic potential. The CD58 molecule encoded by the CD58 gene plays a crucial role in the interaction between T cells and target cells, potentially influencing the function and therapeutic efficacy of CAR-T cells.

Aims:

Analyzing the distribution and types of CD58 mutations in treating B-NHL patients; evaluating the impact of CD58 mutations on CAR-T cell therapy regarding CRS, ICANS, expansion, treatment response, and survival outcomes.

Methods:

We collected the second-generation gene sequencing results of 381 patients treated in our department. Among them, 48 patients were found to have CD58 mutations, and 34 of these patients underwent CAR-T cell therapy from May 2019 to April 2024.16 (47.05%) were male, with a median age of 47.5 years (range 15-75). Diagnoses included DLBCL (n=22), FL (n=1), tFL (n=1), PCNCL (n=2), and PMBCL (n=8). Of the patients, 25/34 (73.5%) were classified as non-GCB subtype, and 30/34 (88.2%) were diagnosed at stage III-IV. Additionally, 12/34 (35.3%) had an IPI score ≥3, and 9/34 (26.5%) had an ECOG score ≥2. Prior treatment history included ≥3 lines in 21/34 (61.8%) patients, with 6/34 (17.6%) having undergone previous autologous transplantation and 10/34 (29.4%) having received prior radiotherapy.

Results：

In our study cohort of 34 patients, detailed mutation site information was available for 25 cases.10/25 in exon 2, 9/25 in exon 3, 4/25 in exon 1, and 2/25 in exon 4. Mutation types included 9/25 stopgain, 5/25 frameshift deletions, 4/25 nonsynonymous SNVs, with functional loss observed in 14/25 cases.The median CAR-T infusion dose was 1.665 × 10^6 cells/kg (range: 0.042-5.2 × 10^6 cells/kg). The median peak CAR-T cell expansion was 37 × 10^6 cells/L, typically occurring on day 11 post-infusion. Among the 34 patients, 24 (70.6%) experienced cytokine release syndrome (CRS), with 3 (8.5%) classified as grade III. Additionally, 2 patients (5.8%) experienced immune effector cell-associated neurotoxicity syndrome (iCANS), with 1 (2.9%) classified as grade III.The best overall response rate (ORR) was 64.7% (complete response [CR] 44.1%, partial response [PR] 20.6%) for all patients. At three months, the ORR was 62%, with a CR rate of 44.1%. Median follow-up was 25.315 months (range 1.64-60.59 months). Median overall survival (OS) was 41.62 months, and progression-free survival (PFS) was 10.59 months. One-year PFS was 48.3% and two-year PFS was 40.2%. One-year OS was 64.4%, and two-year OS was 56.4%.

Conclusions：

Although CD58 plays an important role in the interaction between T cells and target cells, the data observed in this study indicate that mutations in CD58 do not significantly reduce the therapeutic efficacy of CAR-T cells or the treatment responsiveness of patients. This suggests that even in the presence of CD58 mutations, CAR-T cells can still effectively recognize and eliminate B-cell non-Hodgkin lymphoma cells, thereby providing a potential therapeutic option.