肿瘤细胞治疗研究
英文原题：Multiomic profiling of T cell lymphoma after therapy with anti-BCMA CAR T cells and GPRC5D-directed bispecific antibody.
嵌合抗原受体（CAR）T细胞和双特异性T细胞衔接器已成为复发/难治性多发性骨髓瘤治疗中不可或缺的组成部分。
嵌合抗原受体（CAR）T 细胞和双特异性 T 细胞衔接器已成为复发/难治性多发性骨髓瘤治疗中不可或缺的组成部分。我们报告一名 63 岁男性，他因多发性骨髓瘤早期复发接受了 ciltacabtagene autoleucel CAR T 细胞和 GPRC5D CD3 双特异性 talquetamab 治疗。CAR T 治疗九个月后，他出现了有症状的白血病性外周 T 细胞淋巴瘤，伴皮肤和肠道受累。对外周血和骨髓进行的纵向单细胞 RNA 和 T 细胞受体测序显示，有两个高度扩增的携带 CAR 的 T 细胞克隆。这些扩增的克隆表现出耗竭的效应记忆 T 细胞转录特征，且肿瘤本身对 dexamethasone 治疗敏感。这些异常 T 细胞的免疫表型和转录改变类似于 T 大颗粒淋巴细胞白血病。皮肤病变的空间转录组证实了异常表达 CAR 的 T 细胞。全基因组测序揭示了三个不同的整合位点，分别位于 ZGPAT、KPNA4 和多梳相关非编码 RNA 的内含子中。CAR T 治疗前后的全基因组分析提示，一个 TET2 突变的前体细胞在额外的亚克隆特异性杂合性缺失和其他继发机制的驱动下发生克隆性生长。该病例突出了 CAR T 细胞和双特异性 T 细胞衔接器治疗后携带 CAR 的外周 T 细胞淋巴瘤的演变，为从易感造血前体细胞到成熟肿瘤的克隆演变提供了关键见解。
Chimeric antigen receptor (CAR) T cells and bispecific T cell engagers have become integral components in the treatment of relapsed/refractory multiple myeloma. We report a 63-year-old male who received ciltacabtagene autoleucel CAR T cells and the GPRC5D CD3 bispecific talquetamab for early relapse of his multiple myeloma. Nine months after CAR T therapy, he developed a symptomatic leukemic peripheral T cell lymphoma with cutaneous and intestinal involvement. Longitudinal single-cell RNA and T cell receptor sequencing of peripheral blood and bone marrow revealed two hyperexpanded CAR-carrying T cell clones. These expanded clones exhibited an exhausted effector-memory T cell transcriptional signature, and the neoplasm itself was sensitive to dexamethasone treatment. The immunophenotypic and transcriptional alterations of these abnormal T cells resembled those of T-large granular lymphocytic leukemia. Spatial transcriptomes of skin lesions confirmed the aberrant CAR-expressing T cells. Whole-genome sequencing revealed three distinct integration sites, within the introns of ZGPAT, KPNA4 and polycomb-associated noncoding RNAs. Before and after CAR T whole-genome analyses implicated clonal outgrowth of a TET2-mutated precursor propelled by additional subclone-specific loss of heterozygosity and other secondary mechanisms. This case highlights the evolution of a CAR-carrying peripheral T cell lymphoma following CAR T cell and bispecific T cell engager therapy, offering critical insights into the clonal evolution from a predisposed hematopoietic precursor to a mature neoplasm.
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