title: Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model.
abstract: Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting.
authors.affiliation: Johns Hopkins University School of Medicine, Department of Neurosurgery, Baltimore, MD.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mathios
authors.affiliation: Johns Hopkins University School of Medicine, Department of Neurosurgery, Baltimore, MD.|Seoul National University College of Medicine, Department of Neurosurgery, Seoul, Republic of Korea.
authors.forename: Chul-Kee
authors.initials: CK
authors.lastname: Park
authors.affiliation: Altor BioScience Corporation, Miramar, FL.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Marcus
authors.affiliation: Altor BioScience Corporation, Miramar, FL.
authors.forename: Sarah
authors.initials: S
authors.lastname: Alter
authors.affiliation: Altor BioScience Corporation, Miramar, FL.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rhode
authors.affiliation: Altor BioScience Corporation, Miramar, FL.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Jeng
authors.affiliation: Altor BioScience Corporation, Miramar, FL.
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
authors.affiliation: Johns Hopkins University School of Medicine, Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Johns Hopkins University School of Medicine, Department of Neurosurgery, Baltimore, MD.
authors.forename: Michael
authors.initials: M
authors.lastname: Lim
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy; D019409:Interleukin-15 / Q000819:agonists*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D016634:Radiosurgery; D011993:Recombinant Fusion Proteins; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C582303:ALT-803; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019409:Interleukin-15; D061026:Programmed Cell Death 1 Receptor; D011506:Proteins; D011993:Recombinant Fusion Proteins
keywords: ALT-803; IL-15 superagonist; anti-PD-1; glioblastoma