ImportanceThe commercialization of chimeric antigen receptor–T-cell (CAR-T) therapy has changed the landscape of treatment of hematological cancers. Numerous studies from the early 2000s paved the way for cell-based targeted therapeutics, which have been established as practice-changing therapies in lymphoma, leukemia, and multiple myeloma. However, there has been some recent concern about the risk for second primary cancers (SPCs).ObservationsMultiple cases of SPCs arising after CAR-T therapy have been reported to the US Food and Drug Administration. Most SPCs have been negative for the chimeric antigen receptor transgene, with rare reports of transgene-positive cancers. This review summarizes the most salient literature on epidemiology and pathobiology of SPCs after CAR-T therapy. Additionally, a discussion is provided on potential mitigation strategies for SPCs after CAR-T therapies.Conclusions and RelevanceThe results of this review suggest that there are limited data to suggest that inadvertent transgene insertion is associated with SPCs in the post–CAR-T setting. Nonetheless, evidence-based practical solutions and scientific strategies for risk mitigation can be implemented. These include optimization of T-cell manufacturing, application of safer synthetic immunobiology, and implementation of high-fidelity genomic testing, including baseline screening for clonal hematopoiesis. These strategies may inform optimal design of the next generation of CAR-T products that confer minimal risk for SPCs such that the risk-benefit profile remains favorable to proceed with CAR-T administration for eligible patients.

中文翻译：

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嵌合抗原受体-T 细胞治疗后的第二原发癌


重要性嵌合抗原受体-T 细胞 （CAR-T） 疗法的商业化改变了血液癌的治疗格局。2000 年代初期的大量研究为基于细胞的靶向治疗铺平了道路，这些治疗已被确立为改变淋巴瘤、白血病和多发性骨髓瘤实践的疗法。然而，最近人们对第二原发癌 （SPC） 的风险感到担忧。观察结果已向美国食品药品监督管理局报告了多例 CAR-T 治疗后出现的 SPC。大多数 SPC 的嵌合抗原受体转基因呈阴性，转基因阳性癌症的报道很少见。本文总结了 CAR-T 治疗后 SPCs 流行病学和病理生物学方面最突出的文献。此外，还讨论了 CAR-T 治疗后 SPCs 的潜在缓解策略。结论和相关性本综述的结果表明，有限的数据表明，在 CAR-T 后环境中，无意中转基因插入与 SPCs 相关。尽管如此，可以实施基于证据的实用解决方案和降低风险的科学策略。这些包括优化 T 细胞制造、应用更安全的合成免疫学以及实施高保真基因组检测，包括克隆造血的基线筛查。这些策略可以为下一代 CAR-T 产品的优化设计提供信息，这些产品为 SPC 带来最小的风险，从而使风险-收益概况仍然有利于对符合条件的患者进行 CAR-T 给药。