推车
嵌合抗原受体
癌相关成纤维细胞
肿瘤微环境
癌症研究
多发性骨髓瘤
免疫疗法
医学
细胞疗法
成纤维细胞活化蛋白
骨髓
癌症
细胞
免疫学
免疫系统
生物
内科学
工程类
机械工程
遗传学
作者
Reona Sakemura,Mehrdad Hefazi,Elizabeth L. Siegler,Michelle J. Cox,Daniel P. Larson,Michael J. Hansen,Claudia Manriquez Roman,Kendall J. Schick,İsmail Can,Erin E. Tapper,Paulina Horvei,Mohamad M. Adada,Evandro D. Bezerra,Lionel Aurelien Kankeu Fonkoua,Michael W. Ruff,Wendy K. Nevala,Denise K. Walters,Sameer A. Parikh,Yi Lin,Diane F. Jelinek,Neil E. Kay,P. Leif Bergsagel,Saad S. Kenderian
出处
期刊:Blood
[American Society of Hematology]
日期:2022-01-28
卷期号:139 (26): 3708-3721
被引量:78
标识
DOI:10.1182/blood.2021012811
摘要
Abstract Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.
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