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
相关论文
共 50 条
  • [31] CAR T-cell therapy in multiple myeloma: more room for improvement
    Teoh, Phaik Ju
    Chng, Wee Joo
    BLOOD CANCER JOURNAL, 2021, 11 (04)
  • [32] CAR T-cell therapy for multiple myeloma: state of the art and prospects
    van de Donk, Niels W. C. J.
    Usmani, Saad Z.
    Yong, Kwee
    LANCET HAEMATOLOGY, 2021, 8 (06): : E446 - E461
  • [33] CAR T-cell therapy in multiple myeloma: more room for improvement
    Phaik Ju Teoh
    Wee Joo Chng
    Blood Cancer Journal, 11
  • [34] MRD and Plasma Cell Dynamics after CAR T-cell Therapy in Myeloma
    Landgren, Ola
    Kazandjian, Dickran
    BLOOD CANCER DISCOVERY, 2023, 4 (05): : 346 - 348
  • [35] Review of CAR T-Cell Therapy in Multiple Myeloma: A Canadian Perspective
    Shih, Steven Chun-Min
    Bhella, Sita
    CURRENT ONCOLOGY, 2024, 31 (07) : 3949 - 3967
  • [36] Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma
    Choi, Taewoong
    Kang, Yubin
    PHARMACOLOGY & THERAPEUTICS, 2022, 232
  • [37] CAR T-cell therapy: is it prime time in myeloma?
    Sidana, Surbhi
    Shah, Nina
    BLOOD ADVANCES, 2019, 3 (21) : 3473 - 3480
  • [38] CAR T-cell therapy: is it prime time in myeloma?
    Sidana, Surbhi
    Shah, Nina
    HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM, 2019, : 260 - 265
  • [39] Inflammatory Biomarkers and Outcomes in Multiple Myeloma Patients after CAR T-Cell Therapy
    Pan, Darren Denjay
    Mouhieddine, Tarek H.
    Fu, Weijia
    Moshier, Erin
    Parekh, Samir
    Jagannath, Sundar
    Rossi, Adriana C.
    Cho, Hearn Jay
    Richter, Joshua
    Sanchez, Larysa J.
    Thibaud, Santiago
    Rodriguez, Cesar
    Richard, Shambavi
    BLOOD, 2023, 142
  • [40] T-cell exhaustion in multiple myeloma
    Zylka, Krzysztof
    Kubicki, Tadeusz
    Gil, Lidia
    Dytfeld, Dominik
    EXPERT REVIEW OF HEMATOLOGY, 2024, 17 (07) : 295 - 312