{"doi":"10.1136/jitc-2019-000433","title":"Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRII agent: status of preclinical and clinical advances","abstract":"Immunosuppressive entities in the tumor microenvironment (TME) remain a major impediment to immunotherapeutic approaches for a majority of patients with cancer. While the immunosuppressive role of transforming growth factor-β (TGF-β) in the TME is well known, clinical studies to date with anti-TGF-β agents have led to limited success. The bifunctional agent bintrafusp alfa (previously designated M7824) has been developed in an attempt to address this issue. Bintrafusp alfa consists of an IgG 1 targeting programmed death ligand 1 (PD-L1) moiety fused via peptide linkers to the extracellular domain of two TGF-β receptor II molecules designed to ‘trap’ TGF-β in the TME. This agent is able to bring the TGF-β trap to the TME via its anti-PD-L1 component, thus simultaneously attacking both the immunosuppressive PD-L1 and TGF-β entities. A number of preclinical studies have shown bintrafusp alfa capable of (1) preventing or reverting TGF-β-induced epithelial-mesenchymal transition in human carcinoma cells; this alteration in tumor cell plasticity was shown to render human tumor cells more susceptible to immune-mediated attack as well as to several chemotherapeutic agents; (2) altering the phenotype of natural killer and T cells, thus enhancing their cytolytic ability against tumor cells; (3) mediating enhanced lysis of human tumor cells via the antibody-dependent cell-mediated cytotoxicity mechanism; (4) reducing the suppressive activity of T reg cells; (5) mediating antitumor activity in numerous preclinical models and (6) enhancing antitumor activity in combination with radiation, chemotherapy and several other immunotherapeutic agents. A phase I clinical trial demonstrated a safety profile similar to other programmed cell death protein 1 (PD-1)/PD-L1 checkpoint inhibitors, with objective and durable clinical responses. We summarize here preclinical and emerging clinical data in the use of this bispecific and potentially multifunctional agent.","journal":"Journal for ImmunoTherapy of Cancer","year":2020,"id":49559,"datarank":0.8276179344697062,"base_score":5.517452896464707,"endowment":5.517452896464707,"self_citation_contribution":0.8276179344697062,"citation_network_contribution":0.0,"self_endowment_contribution":0.8276179344697062,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":248,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9603,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":239938,"name":"Sofia R. Gameiro","orcid":"0000-0002-2392-8122","position":1,"is_corresponding":false},{"id":239939,"name":"Caroline Jochéms","orcid":"0000-0002-9000-9855","position":2,"is_corresponding":false},{"id":239940,"name":"Renee N. Donahue","orcid":"0000-0002-6828-3073","position":3,"is_corresponding":false},{"id":239941,"name":"Julius Strauss","orcid":"0000-0002-7550-4938","position":4,"is_corresponding":false},{"id":239942,"name":"James L. Gulley","orcid":"0000-0002-6569-2912","position":5,"is_corresponding":false},{"id":231605,"name":"Claudia Palena","orcid":"0000-0002-0445-4486","position":6,"is_corresponding":false},{"id":239943,"name":"Jeffrey Schlom","orcid":"0000-0001-7932-4072","position":7,"is_corresponding":false},{"id":239937,"name":"Hanne Lind","orcid":"0000-0002-9178-2241","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T20:37:28.027635Z","pmid":"32079617","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}