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Cited by 72CAR-T cell therapy researchAcute Lymphoblastic Leukemia researchProtein Degradation and Inhibitors

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Surface Proteomics Reveals CD72 as a Target for In Vitro –Evolved Nanobody-Based CAR-T Cells in KMT2A/MLL1 -Rearranged B-ALL

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Nix, Matthew A., Mandal, Kamal, Geng, Huimin, Paranjape, Neha, Lin, Yu-Hsiu T., Rivera, Jose M., Marcoulis, Makeba, White, Kristie L., Whitman, Jeffrey D., Bapat, Sagar P., Parker, Kevin R., Ramirez, Jonathan, Deucher, Anne, Phojanokong, Paul, Steri, Veronica, Fattahi, Faranak, Hann, Byron C., Satpathy, Ansuman T., Manglik, Aashish, Stieglitz, Elliot, Wiita, Arun P.·2021·Cancer Discovery
DOI 10.1158/2159-8290.cd-20-0242PMC PMC8338785

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Abstract

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. Significance: 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. This article is highlighted in the In This Issue feature, p. 1861

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Metadata

Authors
Nix, M. A., Mandal, K., Geng, H., Paranjape, N., Lin, Y.-H. T., Rivera, J. M., Marcoulis, M., White, K. L., Whitman, J. D., Bapat, S. P., Parker, K. R., Ramirez, J., Deucher, A., Phojanokong, P., Steri, V., Fattahi, F., Hann, B. C., Satpathy, A. T., Manglik, A., Stieglitz, E., & Wiita, A. P.
Affiliations
  • University of California, San Francisco (US)
  • Stanford University (US)
Corresponding author
Wiita, Arun P.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2021-05-16
Volume
11
Issue
8
Pages
2032-2049
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-20-0242
PMC
PMC8338785
OpenAlex
W3137393431
Cited by
72
References
6
Citations by year
2026: 8 · 2025: 18 · 2024: 12 · 2023: 19 · 2022: 12 · 2021: 3
FWCI
4.82
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institutes of Health (DP2 OD022552, K08 CA184116, K08 CA230188, P30 CA082103)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords
CD72, nanobodies, chimeric antigen receptor T cells, CAR T-cell therapy, surface proteomics, SHIP1, B cell receptor signaling, B-cell malignancies
MeSH terms
Receptors, Chimeric Antigen, Antigens, Differentiation, B-Lymphocyte, Humans, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Antigens, CD, Immunotherapy, Adoptive, Antigens, CD19, Proteomics

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