Soluble and membrane-bound interleukin (IL)-15 R[alpha]/IL-15 complexes mediate proliferation of high-avidity central memory CD8+ T cells for adoptive immunotherapy of cancer and infections

• Published in: Clinical and experimental immunology 2016-11, Vol.186 (2), p.249
• Main 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
• Format: Article
• Language: English
• Subjects: Antigens; Cytokines; Cytomegalovirus; Immunotherapy; Lymphocytes; T cell receptors
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.12816

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-15R[alpha] (15R[alpha]/15). We developed a novel in-vitro system for generation of stable 15R[alpha]/15 complexes. Immunologically quantifiable amounts of IL-15 were obtained when both IL-15R[alpha] and IL-15 genes were co-transduced in NIH 3T3 fibroblast-based artificial antigen-presenting cells expressing human leucocyte antigen (HLA) A:0201, [beta]2 microglobulin, CD80, CD58 and CD54 [A2-artificial antigen presenting cell (AAPC)] and a murine pro-B cell line (Baf-3) (A2-AAPC15R[alpha]/15and Baf-315R[alpha]/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-15R[alpha] alone (A2-AAPCR[alpha]) demonstrated stable expression of IL-15R[alpha]; however, when loaded with soluble IL-15 (sIL-15), these cells sequestered 15R[alpha]/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 15R[alpha]/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 15R[alpha]/15, but not sIL-15, sustained in-vitro expansion of CD62L+ and CCR7+ central memory phenotype CMV-CTLs (TCM). 15R[alpha]/15 complexes represent a potent adjuvant for augmenting the efficacy of adoptive immunotherapy. Such cell-bound or soluble 15R[alpha]/15 complexes could be developed for use in combination immunotherapy approaches.