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

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