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

Ledergor, Guy ; Fan, Zenghua ; Wu, Kai ; McCarthy, Elizabeth ; Hyrenius-Wittsten, Axel LU ; Starzinski, Alec ; Chang, Hewitt ; Bridge, Mark ; Kwek, Serena and Cheung, Alexander , et al. (2024) In Blood Advances 8(13). p.3562-3575
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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
in
Blood Advances
volume
8
issue
13
pages
14 pages
publisher
American Society of Hematology
external identifiers
  • scopus:85193908300
  • pmid:38574299
ISSN
2473-9529
DOI
10.1182/bloodadvances.2023012416
language
English
LU publication?
yes
id
1a08f1f8-4f21-4402-abe4-52451617e508
date added to LUP
2025-01-08 15:14:50
date last changed
2025-07-10 06:46:00
@article{1a08f1f8-4f21-4402-abe4-52451617e508,
  abstract     = {{<p>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 &gt;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.</p>}},
  author       = {{Ledergor, Guy and Fan, Zenghua and Wu, Kai and McCarthy, Elizabeth and Hyrenius-Wittsten, Axel and Starzinski, Alec and Chang, Hewitt and Bridge, Mark and Kwek, Serena and Cheung, Alexander and Bylsma, Sophia and Hansen, Erik and Wolf, Jeffrey and Wong, Sandy and Shah, Nina and Roybal, Kole T. and Martin, Thomas and Ye, Chun J. and Fong, Lawrence}},
  issn         = {{2473-9529}},
  language     = {{eng}},
  number       = {{13}},
  pages        = {{3562--3575}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood Advances}},
  title        = {{CD4<sup>+</sup>CAR T-cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR T-cell therapy}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2023012416}},
  doi          = {{10.1182/bloodadvances.2023012416}},
  volume       = {{8}},
  year         = {{2024}},
}