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

被引:5
|
作者
Ledergor, Guy [1 ]
Fan, Zenghua [1 ]
Wu, Kai [1 ,2 ]
Mccarthy, Elizabeth [3 ]
Hyrenius-Wittsten, Axel [4 ,5 ]
Starzinski, Alec [1 ]
Chang, Hewitt [1 ]
Bridge, Mark [1 ]
Kwek, Serena [1 ]
Cheung, Alexander [1 ]
Bylsma, Sophia [1 ]
Hansen, Erik [6 ]
Wolf, Jeffrey [1 ]
Wong, Sandy [1 ]
Shah, Nina [1 ]
Roybal, Kole T. [4 ]
Martin, Thomas [1 ]
Ye, Chun J. [7 ]
Fong, Lawrence [1 ,2 ,7 ]
机构
[1] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA
[2] Fred Hutchinson Canc Ctr, Immunotherapy Integrated Res Ctr, Seattle, WA USA
[3] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA USA
[4] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA USA
[5] Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden
[6] Univ Calif San Francisco, Dept Orthoped Surg, San Francisco, CA USA
[7] Parker Inst Canc Immunotherapy, San Francisco, CA USA
基金
美国国家卫生研究院;
关键词
D O I
10.1182/bloodadvances.2023012416
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 beta. These findings shed new light on the role of cytotoxic CD4+ + T cells in disease progression after CAR T-cell therapy.
引用
收藏
页码:3562 / 3575
页数:14
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