美国斯坦福大学Ash A. Alizadeh团队分析了CAR-T细胞治疗后发生二次肿瘤和T细胞淋巴瘤的风险。相关论文发表在2024年6月13日出版的《新英格兰医学杂志》上。

嵌合抗原受体（CAR）T细胞治疗后发生二次肿瘤的风险，特别是与病毒载体整合相关的T细胞肿瘤风险是一个新出现的问题。

研究组回顾了自2016年以来在他们机构采用过继细胞CAR-T细胞治疗的临床经验，并确定了第二种肿瘤的发生。在一例继发性T细胞淋巴瘤中，使用广泛的分子、遗传和细胞技术来分析患者的肿瘤、CAR-T细胞和正常造血细胞。

研究共包括724名在该中心接受过T细胞治疗的患者。在一名接受axi-cel治疗弥漫性大B细胞淋巴瘤的患者中发现了一种致命的T细胞淋巴瘤，并对这两种淋巴瘤进行了深入分析。每种淋巴瘤都有分子上不同的免疫表型和基因组图谱，但两者都对Epstein–Barr病毒呈阳性，并与DNMT3A和TET2突变克隆性造血有关。使用多种技术未发现致癌逆转录病毒整合的证据。

该研究结果强调了第二种肿瘤的罕见性，并为定义克隆关系和病毒载体监测提供了一个框架。

附：英文原文

Title: Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy

Author: Mark P. Hamilton, Takeshi Sugio, Troy Noordenbos, Shuyu Shi, Philip L. Bulterys, Chih Long Liu, Xiaoman Kang, Mari N. Olsen, Zinaida Good, Saurabh Dahiya, Matthew J. Frank, Bita Sahaf, Crystal L. Mackall, Dita Gratzinger, Maximilian Diehn, Ash A. Alizadeh, David B. Miklos

Issue&Volume: 2024-06-13

Abstract:

BACKGROUND

The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.

METHODS

We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.

RESULTS

A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein–Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.

CONCLUSIONS

Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring.

DOI: NJ202406133902209

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2401361