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Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain.
Mikkilineni, Lekha; Natrakul, Danielle A; Lam, Norris; Manasanch, Elisabet E; Mann, Jennifer; Weissler, Katherine A; Wong, Nathan; Brudno, Jennifer N; Goff, Stephanie L; Yang, James C; Ganaden, Micaela; Patel, Rashmika; Zheng, Zhili; Gartner, Jared J; Martin, Kathryn R; Wang, Hao-Wei; Yuan, Constance M; Lowe, Tyler; Maric, Irina; Shao, Lipei; Jin, Ping; Stroncek, David F; Highfill, Steven L; Rosenberg, Steven A; Kochenderfer, James N.
Afiliación
  • Mikkilineni L; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Natrakul DA; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Lam N; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Manasanch EE; University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Mann J; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Weissler KA; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Wong N; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research in the CCR Collaborative Bioinformatics Resource, National Cancer Institute, Bethesda, MD, USA.
  • Brudno JN; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Goff SL; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Yang JC; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Ganaden M; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Patel R; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Zheng Z; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Gartner JJ; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Martin KR; Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD, USA.
  • Wang HW; Flow Cytometry Unit, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Yuan CM; Flow Cytometry Unit, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Lowe T; Flow Cytometry Unit, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Maric I; Hematology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA.
  • Shao L; Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD, USA.
  • Jin P; Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD, USA.
  • Stroncek DF; Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD, USA.
  • Highfill SL; Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD, USA.
  • Rosenberg SA; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Kochenderfer JN; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: kochendj@mail.nih.gov.
Mol Ther ; 32(2): 503-526, 2024 Feb 07.
Article en En | MEDLINE | ID: mdl-38155568
ABSTRACT
Multiple myeloma (MM) is a rarely curable malignancy of plasma cells. MM expresses B cell maturation antigen (BCMA). We developed a fully human anti-BCMA chimeric antigen receptor (CAR) with a heavy-chain-only antigen-recognition domain, a 4-1BB domain, and a CD3ζ domain. The CAR was designated FHVH33-CD8BBZ. We conducted the first-in-humans clinical trial of T cells expressing FHVH33-CD8BBZ (FHVH-T). Twenty-five patients with relapsed MM were treated. The stringent complete response rate (sCR) was 52%. Median progression-free survival (PFS) was 78 weeks. Of 24 evaluable patients, 6 (25%) had a maximum cytokine-release syndrome (CRS) grade of 3; no patients had CRS of greater than grade 3. Most anti-MM activity occurred within 2-4 weeks of FHVH-T infusion as shown by decreases in the rapidly changing MM markers serum free light chains, urine light chains, and bone marrow plasma cells. Blood CAR+ cell levels peaked during the time that MM elimination was occurring, between 7 and 15 days after FHVH-T infusion. C-C chemokine receptor type 7 (CCR7) expression on infusion CD4+ FHVH-T correlated with peak blood FHVH-T levels. Single-cell RNA sequencing revealed a shift toward more differentiated FHVH-T after infusion. Anti-CAR antibody responses were detected in 4 of 12 patients assessed. FHVH-T has powerful, rapid, and durable anti-MM activity.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptores Quiméricos de Antígenos / Mieloma Múltiple Límite: Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptores Quiméricos de Antígenos / Mieloma Múltiple Límite: Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos