Das Rajat K, O'Connor Roddy S, Grupp Stephan A, Barrett David M
Division of Oncology, Department of Pediatrics.
Department of Pathology and Laboratory Medicine, and.
Blood Adv. 2020 Oct 13;4(19):4653-4664. doi: 10.1182/bloodadvances.2020001797.
Engineered T-cell therapies have demonstrated impressive clinical responses in patients with hematologic malignancies. Despite this efficacy, many patients have a transient persistence of T cells, which can be correlated with transient clinical response. Translational data on T cells from pediatric cancer patients shows a progressive decline in chimeric antigen receptor (CAR) suitability with cumulative chemotherapy regardless of regimen. We investigated the effects of chemotherapy on surviving T cells in vitro, describing residual deficits unique to each agent including mitochondrial damage and metabolic alterations. In the case of cyclophosphamide but not doxorubicin or cytarabine, these effects could be reversed with N-acetylcysteine. Specifically, we observed that surviving T cells could be stimulated, expanded, and transduced with CARs with preserved short-term cytolytic function but at far lower numbers and with residual metabolic deficits. These data have implications for understanding the effects of chemotherapy on mature T cells later collected for adoptive cell therapy, as chemotherapy-exposed T cells may have lingering dysfunction that affects ex vivo adoptive cell therapy manufacturing techniques and, ultimately, clinical efficacy.
工程化T细胞疗法已在血液系统恶性肿瘤患者中展现出令人瞩目的临床反应。尽管有此疗效，但许多患者的T细胞仅短暂存在，这可能与短暂的临床反应相关。来自儿科癌症患者的T细胞的转化数据表明，无论化疗方案如何，随着累积化疗，嵌合抗原受体（CAR）的适用性会逐渐下降。我们在体外研究了化疗对存活T细胞的影响，描述了每种药物独特的残留缺陷，包括线粒体损伤和代谢改变。就环磷酰胺而言，而非阿霉素或阿糖胞苷，这些影响可用N-乙酰半胱氨酸逆转。具体而言，我们观察到存活的T细胞可以被刺激、扩增并用CAR进行转导，其短期溶细胞功能得以保留，但数量要少得多且存在残留的代谢缺陷。这些数据对于理解化疗对随后收集用于过继性细胞治疗的成熟T细胞的影响具有启示意义，因为经化疗的T细胞可能存在持续的功能障碍，这会影响体外过继性细胞治疗的制造技术，并最终影响临床疗效。
