Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain

Lekha Mikkilineni; Danielle A. Natrakul; Norris Lam; Elisabet E. Manasanch; Jennifer Mann; Katherine A. Weissler; Nathan Wong; Jennifer N. Brudno; Stephanie L. Goff; James C. Yang; Micaela Ganaden; Rashmika Patel; Zhili Zheng; Jared J. Gartner; Kathryn R. Martin; Hao Wei Wang; Constance M. Yuan; Tyler Lowe; Irina Maric; Lipei Shao; Ping Jin; David F. Stroncek; Steven L. Highfill; Steven A. Rosenberg; James N. Kochenderfer

doi:10.1016/j.ymthe.2023.12.018

Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain

Lekha Mikkilineni, Danielle A. Natrakul, Norris Lam, Elisabet E. Manasanch, Jennifer Mann, Katherine A. Weissler, Nathan Wong, Jennifer N. Brudno, Stephanie L. Goff, James C. Yang, Micaela Ganaden, Rashmika Patel, Zhili Zheng, Jared J. Gartner, Kathryn R. Martin, Hao Wei Wang, Constance M. Yuan, Tyler Lowe, Irina Maric, Lipei ShaoPing Jin, David F. Stroncek, Steven L. Highfill, Steven A. Rosenberg, James N. Kochenderfer

Lymphoma-Myeloma

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	503-526
Number of pages	24
Journal	Molecular Therapy
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.ymthe.2023.12.018
State	Published - Feb 7 2024

Keywords

CAR
CCR7
clinical trial
immunogenicity
immunotherapy
multiple myeloma therapy
RNA-seq
T cell

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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10.1016/j.ymthe.2023.12.018

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Mikkilineni, L., Natrakul, D. A., Lam, N., Manasanch, E. E., Mann, J., Weissler, K. A., Wong, N., Brudno, J. N., Goff, S. L., Yang, J. C., Ganaden, M., Patel, R., Zheng, Z., Gartner, J. J., Martin, K. R., Wang, H. W., Yuan, C. M., Lowe, T., Maric, I., ... Kochenderfer, J. N. (2024). Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain. Molecular Therapy, 32(2), 503-526. https://doi.org/10.1016/j.ymthe.2023.12.018

Mikkilineni, L, Natrakul, DA, Lam, N, Manasanch, EE, Mann, J, Weissler, KA, Wong, N, Brudno, JN, Goff, SL, Yang, JC, Ganaden, M, Patel, R, Zheng, Z, Gartner, JJ, Martin, KR, Wang, HW, Yuan, CM, Lowe, T, Maric, I, Shao, L, Jin, P, Stroncek, DF, Highfill, SL, Rosenberg, SA & Kochenderfer, JN 2024, 'Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain', Molecular Therapy, vol. 32, no. 2, pp. 503-526. https://doi.org/10.1016/j.ymthe.2023.12.018

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title = "Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain",

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.",

keywords = "CAR, CCR7, clinical trial, immunogenicity, immunotherapy, multiple myeloma therapy, RNA-seq, T cell",

author = "Lekha Mikkilineni and Natrakul, {Danielle A.} and Norris Lam and Manasanch, {Elisabet E.} and Jennifer Mann and Weissler, {Katherine A.} and Nathan Wong and Brudno, {Jennifer N.} and Goff, {Stephanie L.} and Yang, {James C.} and Micaela Ganaden and Rashmika Patel and Zhili Zheng and Gartner, {Jared J.} and Martin, {Kathryn R.} and Wang, {Hao Wei} and Yuan, {Constance M.} and Tyler Lowe and Irina Maric and Lipei Shao and Ping Jin and Stroncek, {David F.} and Highfill, {Steven L.} and Rosenberg, {Steven A.} and Kochenderfer, {James N.}",

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doi = "10.1016/j.ymthe.2023.12.018",

language = "English (US)",

volume = "32",

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T1 - Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain

AU - Mikkilineni, Lekha

AU - Natrakul, Danielle A.

AU - Lam, Norris

AU - Manasanch, Elisabet E.

AU - Mann, Jennifer

AU - Weissler, Katherine A.

AU - Wong, Nathan

AU - Brudno, Jennifer N.

AU - Goff, Stephanie L.

AU - Yang, James C.

AU - Ganaden, Micaela

AU - Patel, Rashmika

AU - Zheng, Zhili

AU - Gartner, Jared J.

AU - Martin, Kathryn R.

AU - Wang, Hao Wei

AU - Yuan, Constance M.

AU - Lowe, Tyler

AU - Maric, Irina

AU - Shao, Lipei

AU - Jin, Ping

AU - Stroncek, David F.

AU - Highfill, Steven L.

AU - Rosenberg, Steven A.

AU - Kochenderfer, James N.

PY - 2024/2/7

Y1 - 2024/2/7

N2 - 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.

AB - 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.

KW - CAR

KW - CCR7

KW - clinical trial

KW - immunogenicity

KW - immunotherapy

KW - multiple myeloma therapy

KW - RNA-seq

KW - T cell

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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

Abstract

Keywords

ASJC Scopus subject areas

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