{"doi":"10.1158/2159-8290.cd-20-0242","title":"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","abstract":"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","journal":"Cancer Discovery","year":2021,"id":152151,"datarank":0.6535063240034389,"base_score":4.356708826689592,"endowment":4.356708826689592,"self_citation_contribution":0.6535063240034389,"citation_network_contribution":0.0,"self_endowment_contribution":0.6535063240034389,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":77,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":646307,"name":"Kamal Mandal","orcid":"0000-0001-6343-6029","position":1,"is_corresponding":false},{"id":272482,"name":"Huimin Geng","orcid":"0000-0001-5339-5446","position":2,"is_corresponding":false},{"id":646308,"name":"Neha Paranjape","orcid":"0000-0001-7788-0497","position":3,"is_corresponding":false},{"id":28921,"name":"Yu-Hsiu T. 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