{"doi":"10.1136/jitc-2022-004725","title":"TEM8 Tri-specific Killer Engager binds both tumor and tumor stroma to specifically engage natural killer cell anti-tumor activity","abstract":"BACKGROUND: The tumor microenvironment contains stromal cells, including endothelial cells and fibroblasts, that aid tumor growth and impair immune cell function. Many solid tumors remain difficult to cure because of tumor-promoting stromal cells, but current therapies targeting tumor stromal cells are constrained by modest efficacy and toxicities. TEM8 is a surface antigen selectively upregulated on tumor and tumor stromal cells, endothelial cells and fibroblasts that may be targeted with specific natural killer (NK) cell engagement. METHODS: A Tri-specific Killer Engager (TriKE) against TEM8-'cam1615TEM8'-was generated using a mammalian expression system. Its function on NK cells was assessed by evaluation of degranulation, inflammatory cytokine production, and killing against tumor and stroma cell lines in standard co-culture and spheroid assays. cam1615TEM8-mediated proliferation and STAT5 phosphorylation in NK cells was tested and compared with T cells by flow cytometry. NK cell proliferation, tumor infiltration, and tumor and tumor-endothelium killing by cam1615TEM8 and interleukin-15 (IL-15) were assessed in NOD scid gamma (NSG) mice. RESULTS: cam1615TEM8 selectively stimulates NK cell degranulation and inflammatory cytokine production against TEM8-expressing tumor and stromal cell lines. The increased activation translated to superior NK cell killing of TEM8-expressing tumor spheroids. cam1615TEM8 selectively stimulated NK cell but not T cell proliferation in vitro and enhanced NK cell proliferation, survival, and tumor infiltration in vivo. Finally, cam1615TEM8 stimulated NK cell killing of tumor and tumor endothelial cells in vivo. CONCLUSIONS: Our findings indicate that the cam1615TEM8 TriKE is a novel anti-tumor, anti-stroma, and anti-angiogenic cancer therapy for patients with solid tumors. This multifunctional molecule works by selectively targeting and activating NK cells by costimulation with IL-15, and then targeting that activity to TEM8+ tumor cells and TEM8+ tumor stroma.","journal":"Journal for ImmunoTherapy of Cancer","year":2022,"id":245530,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9708,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":302945,"name":"Laura E. Bendzick","orcid":"0000-0002-3197-5885","position":1,"is_corresponding":false},{"id":747142,"name":"Rachel Hopps","orcid":"0000-0001-7415-9522","position":2,"is_corresponding":false},{"id":881292,"name":"Marissa Kauffman","orcid":null,"position":3,"is_corresponding":false},{"id":302942,"name":"Behiye Kodal","orcid":"0000-0002-0898-2446","position":4,"is_corresponding":false},{"id":881293,"name":"Yvette Soignier","orcid":null,"position":5,"is_corresponding":false},{"id":302944,"name":"Peter Hinderlie","orcid":"0000-0002-0816-956X","position":6,"is_corresponding":false},{"id":881294,"name":"Joshua T. Walker","orcid":null,"position":7,"is_corresponding":false},{"id":303636,"name":"Todd Lenvik","orcid":null,"position":8,"is_corresponding":false},{"id":302947,"name":"Melissa A. Geller","orcid":"0000-0003-4591-620X","position":9,"is_corresponding":false},{"id":302950,"name":"Jeffrey S. Miller","orcid":"0000-0002-0339-4944","position":10,"is_corresponding":false},{"id":302941,"name":"Martin Felices","orcid":"0000-0002-5945-0634","position":11,"is_corresponding":false},{"id":302946,"name":"Michał F. Kamiński","orcid":"0000-0002-9714-6457","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T00:23:39.284121Z","pmid":"36162918","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":[]}