CD4+ CAR T-cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR T-cell therapy

Author:

Ledergor Guy1ORCID,Fan Zenghua1ORCID,Wu Kai12,McCarthy Elizabeth3ORCID,Hyrenius-Wittsten Axel45ORCID,Starzinski Alec1ORCID,Chang Hewitt1ORCID,Bridge Mark1ORCID,Kwek Serena1ORCID,Cheung Alexander1,Bylsma Sophia1,Hansen Erik6,Wolf Jeffrey1,Wong Sandy1,Shah Nina1,Roybal Kole T.47,Martin Thomas1,Ye Chun J.37,Fong Lawrence127ORCID

Affiliation:

1. 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA

2. 2Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA

3. 3Institute for Human Genetics, University of California, San Francisco, San Francisco, CA

4. 4Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA

5. 5Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden

6. 6Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA

7. 7Parker Institute for Cancer Immunotherapy, San Francisco, CA

Abstract

Abstract Multiple myeloma is characterized by frequent clinical relapses after conventional therapy. Recently, chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA) has been established as a treatment option for patients with relapsed or refractory disease. However, although >70% of patients initially respond to this treatment, clinical relapse and disease progression occur in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune-intrinsic mechanisms may contribute to this resistance. Although there were no preexisting T-cell features associated with clinical outcomes, we found that patients with a durable response to CAR T-cell treatment had greater persistence of their CAR T cells than patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T-effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR T cells. These cells expand in vivo early after infusion but express exhaustion markers (hepatitis A virus cellular receptor 2 [HAVCR2] and T-cell immunoglobulin and mucin domain-containing-3 [TIGIT]) and remain polyclonal. Finally, we demonstrate that nonclassical monocytes are enriched in the myeloma niche and may induce CAR T-cell dysfunction through mechanisms that include transforming growth factor β. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR T-cell therapy.

Publisher

American Society of Hematology

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3