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. (31st August 2016)

• Record Type: Journal Article
• Authors: Hasan, A. N.; Selvakumar, A.; Shabrova, E.; Liu, X.‐R.; Afridi, F.; Heller, G.; Riviere, I.; Sadelain, M.; Dupont, B.; O'Reilly, R. J.
• Is Part Of: Clinical and experimental immunology. Volume 186:Number 2(2016:Nov.)
• Page Start: 249
• Page End: 265
• Publication Date: 2016-08-31
• Subjects: adoptive immunotherapy -- cancer immunotherapy -- cytokine -- immunomodulation -- T cell memory -- immune adjuvant; Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.12816
• Languages: English
• ISSNs: 0009-9104

Abstract

Summary: 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, β2 microglobulin, CD80, CD58 and CD54 [A2‐artificial antigen presenting cell (AAPC)] and a murine pro‐B cell line (Baf‐3) (A2‐AAPC 15Rα/15 and Baf‐3 15Rα/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‐AAPC Rα ) 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 − 13 M 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. Abstract : IL‐15 promotes preferential enrichment and expansion of highly functional epitope specific CD8+ T‐cells in vitro. These effects are specifically pronounced when IL‐15 is bound to IL‐15Rα as a complex, either soluble or cell membrane bound. IL‐15Rα/IL‐15 complexes, but not IL‐15 alone, support expansion of memory phenotype T‐cells over 28 days of continuous antigenic stimulation and therefore represent a potent adjunct for augmenting the activity of immunotherapeutic approaches.