Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain
Published by Elsevier Inc..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:32 |
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| Enthalten in: |
Molecular therapy : the journal of the American Society of Gene Therapy - 32(2024), 2 vom: 07. Feb., Seite 503-526 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mikkilineni, Lekha [VerfasserIn] |
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| Links: |
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| Themen: |
CAR |
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| Anmerkungen: |
Date Completed 14.02.2024 Date Revised 15.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ymthe.2023.12.018 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366462091 |
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| 100 | 1 | |a Mikkilineni, Lekha |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain |
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| 520 | |a Published by Elsevier Inc. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Natrakul, Danielle A |e verfasserin |4 aut | |
| 700 | 1 | |a Lam, Norris |e verfasserin |4 aut | |
| 700 | 1 | |a Manasanch, Elisabet E |e verfasserin |4 aut | |
| 700 | 1 | |a Mann, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Weissler, Katherine A |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Nathan |e verfasserin |4 aut | |
| 700 | 1 | |a Brudno, Jennifer N |e verfasserin |4 aut | |
| 700 | 1 | |a Goff, Stephanie L |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, James C |e verfasserin |4 aut | |
| 700 | 1 | |a Ganaden, Micaela |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Rashmika |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Zhili |e verfasserin |4 aut | |
| 700 | 1 | |a Gartner, Jared J |e verfasserin |4 aut | |
| 700 | 1 | |a Martin, Kathryn R |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hao-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Constance M |e verfasserin |4 aut | |
| 700 | 1 | |a Lowe, Tyler |e verfasserin |4 aut | |
| 700 | 1 | |a Maric, Irina |e verfasserin |4 aut | |
| 700 | 1 | |a Shao, Lipei |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Stroncek, David F |e verfasserin |4 aut | |
| 700 | 1 | |a Highfill, Steven L |e verfasserin |4 aut | |
| 700 | 1 | |a Rosenberg, Steven A |e verfasserin |4 aut | |
| 700 | 1 | |a Kochenderfer, James N |e verfasserin |4 aut | |
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