Purpose Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. Patients and Methods We performed a first in-human trial of Escherichia coli–produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Results Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. Conclusion IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.

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Vaccine efficacy is determined largely by cellular and humoral immunity as well as long-lasting immunological memory. IL-2 and IL-15 were evaluated in vaccinia vectors expressing HIV gp160 for the establishment of an effective vaccine strategy. Both IL-2 and IL-15 in the vaccinia vector induced strong and long-lasting antibody-mediated immunity as well as a short-term cytotoxic T cell response against HIV gp120. In addition, IL-15 also supported robust CD8 ؉ T cell-mediated long-term immunity, whereas the CD8 ؉ T cell-mediated immunity induced by IL-2 was short-lived. Moreover, we found that the cytokine milieu at the time of priming had surprisingly persistent effects on the character of the memory CD8 T cells long afterward with respect to their fate, functional activities, cytokine receptor expression, and antigen-independent proliferation.

Antigen-specific CD8 ϩ T cells can be programmed in the immune induction phase (3-5). CD4 ϩ help is needed for induction of long-lived memory CD8ϩ T cells (6, 7). The results of early programming are more profound in secondary responses: CD8 ϩ T cells primed in the absence of CD4 ϩ helper T cells undergo tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and show poor long term memory (8, 9). Thus, understanding the mechanisms by which help from CD4 ϩ T cells prevents CD8 ϩ T cell death and enhances the maintenance of memory CD8 ϩ T cells is critical for developing new vaccines.In addition to the maintenance of CD8 ϩ memory T cells (10-15), we previously found that additional IL-15 provided by a vaccine vector only during priming induced long-lived memory CD8 ϩ T cells (5) and contributed to the long-term avidity maturation of CD8 ϩ T cells (16). These findings suggest that IL-15 contributes to programming of CD8 ϩ T cells to be long-lived cells that can further expand on reexposure to antigen. Therefore, we hypothesized that CD8 ϩ T cells programmed with IL-15 only during priming, even in the absence of CD4 ϩ helper T cells, may overcome TRAIL-mediated apoptosis during secondary responses and persist longer. We also hypothesized that one mechanism by which CD4 ϩ helper T cells help CD8 ϩ T cells is to stimulate IL-15 production by the antigen presenting cells (APCs), including dendritic cells (DCs).Here, we show that IL-15 provided by the vaccine can replace CD4 ϩ helper T cells in inducing long-lasting antigen-specific CD8 ϩ T cells that can efficiently respond to secondary responses.Conversely, help was less effective when DCs did not produce IL-15. Thus, we conclude that IL-15 codelivered with vaccines can overcome CD4 ϩ helper T cell deficiency and that IL-15 may be one mediator of help. These new findings will be important for developing new vaccines against cancers and viral infections, especially those such as HIV that result in diminished CD4 ϩ T cell help. Results IL-15 Substitutes for CD4 ؉ Help in CD8 ؉ T Cell Priming for Long-LivedMemory. To test whether IL-15 can substitute for CD4 ϩ T cells in the induction of longer-lived antigen-specific CD8 ϩ T cells, animals, either CD4-depleted or undepleted, were immunized with recombinant vaccinia viruses expressing HIVgp160 (vPE16) or .CD4 ϩ T cell-undepleted animals immunized with vPE16 maintained P18-I10-specific CD8 ϩ T cells (measured directly ex vivo without restimulation) for 1 year (Fig. 1A). Animals immunized with vPE16-IL-15 had a higher percentage of long-lasting memory CD8 ϩ T cells than those without IL-15 (percentage of peak response remaining, 23% vs. 16%), indicating that IL-15 provided by the vaccine vector contributes to the enhanced induction of long-lasting memory CD8 ϩ CTL in WT animals and that endogenous IL-15 may be limiting. In contrast, in CD4-depleted animals, the majority of the CD8 ϩ T cells induced by vPE16 disappeared shortly after the primary response, with Ͻ1% of the peak response remaining at...

Interleukin-15 (IL-15) is a pleiotropic cytokine with a broad range of biological functions in many diverse cell types. It plays a major role in the development of inflammatory and protective immune responses to microbial invaders and parasites by modulating immune cells of both the innate and adaptive immune systems. This review provides an overview of the mechanisms by which IL-15 modulates the host response to infectious agents and its utility as a cytokine adjuvant in vaccines against infectious pathogens.

Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)-and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells.Here we report that 10-50 g/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short-and longlasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T-and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. IntroductionCytokines belonging to the ␥-chain family represent a promising tool for the treatment of certain human diseases in which the immune system is suppressed like HIV or cancer. Thus, boosting immunity in these patients may be beneficial and result in improved treatment. is part of the ␥-chain family of cytokines and exerts multiple effects on different populations of the immune system. For instance, it is necessary for natural killer (NK)-cell development, since IL-15-deficient mice lack NK cells 1,2 ; it acts as an NK growth factor by promoting the differentiation of CD56 ϩ cytokine-producing NK cells to CD56 Ϫ CD16 ϩ cytotoxic NK cells. 3 Conversely, IL-15 is not required for T-cell development but exerts a fundamental role in determining their survival and homeostasis in the periphery. IL-15 Ϫ/Ϫ or IL-15 receptor ␣ chain (IL-15R␣) Ϫ/Ϫ mice display slightly reduced numbers of naive T cells and a selective deficiency of memory T cells. 1,2 Indeed, IL-15 is important for memory T-cell homeostasis as it mediates the expansion and maintenance of memoryphenotype CD8 ϩ T cells 4 and the homeostatic proliferation of antigen-specific CD8 ϩ T cells, while survival is mainly mediated by IL-7 in the latter case. 4,5 IL-15 also acts on memory CD4 ϩ T cells and cooperates with IL-7 in inducing their expansion in nonlymphopenic conditions. 4 A unique biological mechanism governs IL-15 functions in vivo, as the cytokine is transpresented by cells bearing IL-15R␣ chain to neighboring cells, which in turn, express CD122 (IL-15R␤ chain) and CD132 (common ␥ chain, shared by other cytokines such as IL-2, IL-7, IL-9, and IL-21), which are necessary for IL-15 signaling in responding cells 6,7 ). Activated monocytes or dendritic cells (DCs) can express IL-15R␣ and produce the cytokine at the same time; IL-15 can thus be mounted on the receptor in intracellular compartment and then translocated to the cell surface...

autoimmunity ͉ celiac disease ͉ immunotherapy ͉ interleukine 15 receptor C eliac disease (CD) is an immune-mediated enteropathy triggered by the consumption of gluten-containing cereals by genetically susceptible individuals carrying the HLA class II DQ alleles that encode DQ2 or DQ8 molecules (1, 2). Gluten peptides resulting from partial digestion of dietary cerealderived prolamines are presented by the antigen-presenting cells in the lamina propria bearing HLA-DQ2 or HLA-DQ8 class II molecules to cognate gluten-specific CD4 ϩ

Purpose: The first-in-human clinical trial with human bolus i.v. infusion IL-15 (rhIL-15) was limited by treatment-associated toxicity. Here, we report toxicity, immunomodulation, and clinical activity of rhIL-15 administered as a 10-day continuous intravenous infusion (CIV) to patients with cancers in a phase I trial. Patients and Methods: Patients received treatment for 10 days with CIV rhIL-15 in doses of 0.125, 0.25, 0.5, 1, 2, or 4 mcg/kg/day. Correlative laboratory tests included IL-15 pharmacokinetic (PK) analyses, and assessment of changes in lymphocyte subset numbers. Results: Twenty-seven patients were treated with rhIL-15; 2 mcg/kg/day was identified as the maximum tolerated dose (MTD). There were 8 serious adverse events including 2 bleeding events, papilledema, uveitis, pneumonitis, duodenal erosions and 2 deaths (one due to likely drug-related gastrointestinal ischemia). Evidence of antitumor effects were observed in several patients, but stable disease was the best response noted. Patients in 2 mcg/kg/day group had a 5.8-fold increase in number of circulating CD8+ T cells, 38-fold increase in total NK cells, and 358-fold increase in CD56bright NK cells. Serum IL-15 concentrations were markedly lower during the last 3 days of infusion. Conclusion: This phase I trial identified the MTD for CIV rhIL-15 and defined a treatment regimen that produced significant expansions of CD8+ T and NK effector cells in circulation and tumor deposits. This regimen has identified several biological features, including dramatic increases in numbers of NK cells, supporting trials of IL-15 with anticancer monoclonal antibodies to increase antibody-dependent cell-mediated cytotoxicity (ADCC) and anticancer efficacy.