title: Cooperative therapeutic anti-tumor effect of IL-15 agonist ALT-803 and co-targeting soluble NKG2D ligand sMIC.
abstract: Shedding of the human NKG2D ligand MIC (MHC class I-chain-related molecule) from tumor cell surfaces correlates with progression of many epithelial cancers. Shedding-derived soluble MIC (sMIC) enables tumor immune escape through multiple immune suppressive mechanisms, such as disturbing natural killer (NK) cell homeostatic maintenance, impairing NKG2D expression on NK cells and effector T cells, and facilitating the expansion of arginase I+ myeloid suppressor cells. Our recent study has demonstrated that sMIC is an effective cancer therapeutic target. Whether targeting tumor-derived sMIC would enhance current active immunotherapy is not known. Here, we determined the in vivo therapeutic effect of an antibody co-targeting sMIC with the immunostimulatory IL-15 superagonist complex, ALT-803, using genetically engineered transplantable syngeneic sMIC+ tumor models. We demonstrate that combined therapy of a nonblocking antibody neutralizing sMIC and ALT-803 improved the survival of animals bearing sMIC+ tumors in comparison to monotherapy. We further demonstrate that the enhanced therapeutic effect with combined therapy is through concurrent augmentation of NK and CD8 T cell anti-tumor responses. In particular, expression of activation-induced surface molecules and increased functional potential by cytokine secretion are improved greatly by the administration of combined therapy. Depletion of NK cells abolished the cooperative therapeutic effect. Our findings suggest that administration of the sMIC-neutralizing antibody can enhance the anti-tumor effects of ALT-803. With ALT-803 currently in clinical trials to treat progressive solid tumors, the majority of which are sMIC+, our findings provide a rationale for co-targeting sMIC to enhance the therapeutic efficacy of ALT-803 or other IL-15 agonists.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Fahmin
authors.initials: F
authors.lastname: Basher
authors.affiliation: Altor BioSciences Corporation, Miramar, FL, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Jeng
authors.affiliation: Altor BioSciences Corporation, Miramar, FL, USA.
authors.forename: Hing
authors.initials: H
authors.lastname: Wong
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.|Cancer Immunology Program, Hollings Cancer Center, Charleston, SC, USA.|CanCure LLC, Everett, WA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D019409:Interleukin-15 / Q000819:agonists* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: C582303:ALT-803; D057134:Antibodies, Neutralizing; D015395:Histocompatibility Antigens Class I; D019409:Interleukin-15; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011506:Proteins; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma
keywords: ALT-803; soluble NKG2D; therapy; tumor