改变方向:将嵌合抗原受体T细胞疗法扩展至高危浆细胞异常增殖性疾病

Changing lanes: extending CAR T-cell therapy to high-risk plasma cell dyscrasias.

作者信息

Morgan Heather T, Derman Benjamin A, Ma Hong, Kumar Shaji K

机构信息

Clinical Development, Oricell Therapeutics, Roseland, NJ, United States.

Section of Hematology/Oncology, University of Chicago, Chicago, IL, United States.

出版信息

Front Immunol. 2025 Apr 8;16:1558275. doi: 10.3389/fimmu.2025.1558275. eCollection 2025.

Abstract

Chimeric antigen receptor (CAR) cellular therapies have advanced outcomes in challenging hematologic malignancies like leukemia, lymphoma, and multiple myeloma. Plasma cell-directed CAR T-cell therapies have been particularly beneficial in multiple myeloma, suggesting that these agents may have a role in other challenging plasma cell disorders such as systemic AL amyloidosis and plasma cell leukemia. AL amyloidosis is a monoclonal plasma cell disorder resulting in the deposition of protein fibrils that compromise end-organ function. Delays in diagnosis can result in end-organ dysfunction and organ failure, making designing and completing treatment difficult. Plasma cell leukemia (PCL) is a rare and highly challenging malignancy with dismal survival outcomes despite aggressive therapy. Both diagnoses are currently treated with regimens borrowed from myeloma: a combination of novel agents and chemotherapy induction, then autologous stem cell transplantation (ASCT), with the current practice trending towards consolidation and maintenance. Unfortunately, only 20% of AL amyloidosis patients are transplant-eligible at diagnosis. Those transplant-ineligible (TIE) patients are treated with combination induction chemotherapy, which may be limited by worsening disease-related end-organ dysfunction. Plasma cell leukemia patients are still very likely to relapse after this intensive and prolonged therapy. Despite the promise of a shorter course of therapy, CAR T-cell therapies directed against plasma cells have not been rigorously investigated in patients with AL amyloidosis or PCL; most trials of MM have excluded these patients. Herein, we describe current treatment paradigms for AL amyloidosis and PCL and review the evidence for CAR T-cell therapies in these challenging plasma cell disorders. Further investigation into CAR T-cell therapies for plasma cell disorders other than multiple myeloma is warranted.

摘要

嵌合抗原受体(CAR)细胞疗法在白血病、淋巴瘤和多发性骨髓瘤等具有挑战性的血液系统恶性肿瘤中取得了更好的治疗效果。针对浆细胞的CAR T细胞疗法在多发性骨髓瘤中尤其有益,这表明这些药物可能在其他具有挑战性的浆细胞疾病中发挥作用,如系统性AL淀粉样变性和浆细胞白血病。AL淀粉样变性是一种单克隆浆细胞疾病,会导致损害终末器官功能的蛋白纤维沉积。诊断延迟会导致终末器官功能障碍和器官衰竭,使得设计和完成治疗变得困难。浆细胞白血病(PCL)是一种罕见且极具挑战性的恶性肿瘤,尽管进行了积极治疗,其生存结果仍然不佳。目前这两种疾病的治疗方案均借鉴自骨髓瘤:采用新型药物与化疗诱导相结合的方法,然后进行自体干细胞移植(ASCT),目前的治疗趋势是巩固和维持治疗。不幸的是,只有20%的AL淀粉样变性患者在诊断时符合移植条件。那些不符合移植条件(TIE)的患者接受联合诱导化疗,这可能会受到疾病相关终末器官功能障碍恶化的限制。浆细胞白血病患者在这种强化和长期治疗后仍很可能复发。尽管有望采用更短疗程的治疗方法,但针对浆细胞的CAR T细胞疗法尚未在AL淀粉样变性或PCL患者中进行严格研究;大多数MM试验都排除了这些患者。在此,我们描述了AL淀粉样变性和PCL的当前治疗模式,并回顾了CAR T细胞疗法在这些具有挑战性的浆细胞疾病中的证据。有必要对除多发性骨髓瘤之外的浆细胞疾病的CAR T细胞疗法进行进一步研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a86/12011880/18f7d924aa9a/fimmu-16-1558275-g001.jpg

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