title: Soluble and membrane-bound interleukin (IL)-15 Rα/IL-15 complexes mediate proliferation of high-avidity central memory CD8+T cells for adoptive immunotherapy of cancer and infections.
abstract: The lack of persistence of infused T cells is a principal limitation of adoptive immunotherapy in man. Interleukin (IL)-15 can sustain memory T cell expansion when presented in complex with IL-15Rα (15Rα/15). We developed a novel in-vitro system for generation of stable 15Rα/15 complexes. Immunologically quantifiable amounts of IL-15 were obtained when both IL-15Rα and IL-15 genes were co-transduced in NIH 3T3 fibroblast-based artificial antigen-presenting cells expressing human leucocyte antigen (HLA) A:0201, β2microglobulin, CD80, CD58 and CD54 [A2-artificial antigen presenting cell (AAPC)] and a murine pro-B cell line (Baf-3) (A2-AAPC15Rα/15and Baf-315Rα/15). Transduction of cells with IL-15 alone resulted in only transient expression of IL-15, with minimal amounts of immunologically detectable IL-15. In comparison, cells transduced with IL-15Rα alone (A2-AAPCRα) demonstrated stable expression of IL-15Rα; however, when loaded with soluble IL-15 (sIL-15), these cells sequestered 15Rα/15 intracellularly and also demonstrated minimal amounts of IL-15. Human T cells stimulated in vitro against a viral antigen (CMVpp65) in the presence of 15Rα/15 generated superior yields of high-avidity CMVpp65 epitope-specific T cells [cytomegalovirus-cytotoxic T lymphocytes (CMV-CTLs)] responding to ≤ 10- 13M peptide concentrations, and lysing targets cells at lower effector : target ratios (1 : 10 and 1 : 100), where sIL-15, sIL-2 or sIL-7 CMV-CTLs demonstrated minimal or no activity. Both soluble and surface presented 15Rα/15, but not sIL-15, sustained in-vitro expansion of CD62L+and CCR7+central memory phenotype CMV-CTLs (TCM). 15Rα/15 complexes represent a potent adjuvant for augmenting the efficacy of adoptive immunotherapy. Such cell-bound or soluble 15Rα/15 complexes could be developed for use in combination immunotherapy approaches.
authors.affiliation: Department of Pediatrics, Division of Bone Marrow Transplantation.|Department of Pediatrics, Immunology Program, Sloan-Kettering Institute.
authors.forename: A N
authors.initials: AN
authors.lastname: Hasan
authors.affiliation: Department of Pediatrics, Immunology Program, Sloan-Kettering Institute.
authors.forename: A
authors.initials: A
authors.lastname: Selvakumar
authors.affiliation: Department of Pediatrics, Division of Bone Marrow Transplantation.
authors.forename: E
authors.initials: E
authors.lastname: Shabrova
authors.affiliation: Department of Pediatrics, Immunology Program, Sloan-Kettering Institute.
authors.forename: X-R
authors.initials: XR
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Division of Bone Marrow Transplantation.
authors.forename: F
authors.initials: F
authors.lastname: Afridi
authors.affiliation: Department of Epidemiology and Biostatistics.
authors.forename: G
authors.initials: G
authors.lastname: Heller
authors.affiliation: The Center for Cell Engineering.
authors.forename: I
authors.initials: I
authors.lastname: Riviere
authors.affiliation: The Center for Cell Engineering.
authors.forename: M
authors.initials: M
authors.lastname: Sadelain
authors.affiliation: Department of Pediatrics, Immunology Program, Sloan-Kettering Institute.|Division of Bone Marrow Transplantation, Memorial Sloan-Kettering Cancer Center New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Dupont
authors.affiliation: Department of Pediatrics, Division of Bone Marrow Transplantation. oreillyr@mskcc.org.|Department of Pediatrics, Immunology Program, Sloan-Kettering Institute. oreillyr@mskcc.org.|The Center for Cell Engineering. oreillyr@mskcc.org.
authors.forename: R J
authors.initials: RJ
authors.lastname: O'Reilly
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002461:Cell Line, Transformed; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D007239:Infections / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D011485:Protein Binding; D053647:Receptors, Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D019409:Interleukin-15; D053647:Receptors, Interleukin-15
keywords: T cell memory; adoptive immunotherapy; cancer immunotherapy; cytokine; immune adjuvant; immunomodulation