Surface Proteomics Reveals CD72 as a Target for <i>In Vitro</i>–Evolved Nanobody-Based CAR-T Cells in <i>KMT2A/MLL1</i>-Rearranged B-ALL
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- Matthew A. Nix
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Kamal Mandal
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Huimin Geng
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Neha Paranjape
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Yu-Hsiu T. Lin
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Jose M. Rivera
- 2Department of Pediatrics, University of California, San Francisco, San Francisco, California.
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- Makeba Marcoulis
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Kristie L. White
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Jeffrey D. Whitman
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Sagar P. Bapat
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Kevin R. Parker
- 3Department of Pathology, Stanford University, Stanford, California.
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- Jonathan Ramirez
- 4Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California.
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- Anne Deucher
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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- Paul Phojanokong
- 5Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
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- Veronica Steri
- 5Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
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- Faranak Fattahi
- 4Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California.
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- Byron C. Hann
- 5Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
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- Ansuman T. Satpathy
- 3Department of Pathology, Stanford University, Stanford, California.
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- Aashish Manglik
- 6Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.
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- Elliot Stieglitz
- 2Department of Pediatrics, University of California, San Francisco, San Francisco, California.
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- Arun P. Wiita
- 1Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
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説明
<jats:title>Abstract</jats:title> <jats:sec> <jats:title/> <jats:p>Alternative strategies are needed for patients with B-cell malignancy relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis KMT2A/MLL1-rearranged (MLLr) B-cell acute lymphoblastic leukemia (B-ALL), which we further found to be expressed in other B-cell malignancies. Using a recently described, fully in vitro system, we selected synthetic CD72-specific nanobodies, incorporated them into chimeric antigen receptors (CAR), and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Taking advantage of the role of CD72 in inhibiting B-cell receptor signaling, we found that SHIP1 inhibition increased CD72 surface density. We establish that CD72-nanobody CAR-T cells are a promising therapy for MLLr B-ALL.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>Patients with MLLr B-ALL have poor prognoses despite recent immunotherapy advances. Here, surface proteomics identifies CD72 as being enriched on MLLr B-ALL but also widely expressed across B-cell cancers. We show that a recently described, fully in vitro nanobody platform generates binders highly active in CAR-T cells and demonstrate its broad applicability for immunotherapy development.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 1861</jats:p> </jats:sec>
収録刊行物
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- Cancer Discovery
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Cancer Discovery 11 (8), 2032-2049, 2021-05-16
American Association for Cancer Research (AACR)
