Combining MCL-1 inhibition and CD37-directed chimeric antigen receptor T cells as an effective strategy to target T-cell lymphoma

IF 13.4 1区 医学 Q1 HEMATOLOGY
Tayla B. Heavican-Foral, Felix Korell, Irene Scarfò, Caroline R. M. Wiggers, Allen Thayakumar B, Zachary Eisenbies, Foster Powers, Justin Hegel, Jianlin Liu, Steffen Kulp, Harrison Silva, Gongwei Wu, Anthony Letai, Kimberly Stegmaier, Jens G. Lohr, David M. Weinstock, Marcela V. Maus, Birgit Knoechel
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引用次数: 0

Abstract

Chimeric antigen receptor (CAR) T cell therapy has not yet been realized for T-cell lymphomas (TCL), partially due to challenges in identifying tumor-specific antigens. We previously reported selective expression of CD37 on malignant T cells in a subset of TCL. Herein, we demonstrate CAR-37 T cells specifically target CD37-positive TCL in part by activating the intrinsic apoptotic pathway. To maximize therapeutic index, we identified selective/targetable BH3 dependences in individual TCL models and combined with CAR-37 T cells. We show that BH3 mimetics do not alter CD37 antigen binding capacity on TCL and have minimal effects on CAR-37 T-cell phenotype or function. In TCL models with dependence on MCL-1, combining CAR-37 T cells and the MCL-1 inhibitor AZD5991 increases anti-TCL response and prolongs survival of xenografted mice. These findings suggest that personalized selection of BH3 mimetic/CAR-T combinations could maximize the therapeutic index for patients with TCL and possibly other diseases.

Abstract Image

Abstract Image

MCL-1抑制与cd37靶向嵌合抗原受体T细胞联合作为靶向T细胞淋巴瘤的有效策略
嵌合抗原受体(CAR) T细胞治疗尚未实现T细胞淋巴瘤(TCL),部分原因是在识别肿瘤特异性抗原方面存在挑战。我们之前报道了CD37在TCL亚型的恶性T细胞上的选择性表达。在此,我们证明car - 37t细胞通过激活内在凋亡途径特异性靶向cd37阳性TCL。为了最大限度地提高治疗指数,我们在单个TCL模型中鉴定了选择性/靶向BH3依赖性,并与CAR-37 T细胞联合使用。我们发现BH3模拟物不会改变CD37抗原在TCL上的结合能力,对CAR-37 t细胞表型或功能的影响最小。在依赖MCL-1的TCL模型中,CAR-37 T细胞与MCL-1抑制剂AZD5991联合使用可增加抗TCL反应,延长异种移植小鼠的存活时间。这些发现表明,个性化选择BH3模拟物/CAR-T组合可以最大限度地提高TCL患者的治疗指数,也可能是其他疾病。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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