ZIB BC 010906 (ZIB) | |||
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Title | Interleukin-15 Production for Treatment of Patients with Metastatic Malignancy | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Waldmann, Thomas | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,949,215 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Bioengineering (100.0%) Cancer (100.0%) Metastasis (100.0%) |
Kidney Disease (40.0%) Leukemia (10.0%) Melanoma (40.0%) Non Hodgkins Lymphoma (10.0%) Urinary System (40.0%) Kidney Cancer (40.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
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Abstract | |||
Waldmann co-discovered the cytokine IL-15 and elucidated its role in the development of NK cells and CD8 memory phenotype T-cells. He demonstrated that IL-15 acts as a cell-membrane associated molecule, that IL-15R alpha on antigen-presenting cells (APCs) presents IL-15 in trans to NK and CD8 T-cells. Waldmann demonstrated IL-15 to be of value in 4 murine models of neoplasia. IL-15 administered by continuous intravenous infusion (CIV) at 20 mcg/kg for 10 days to rhesus macaques was associated with an 80-100-fold increase in the number of circulating CD8 effector memory T-cells. With Kevin Conlon Waldmann executed and reported a first-in-human phase I study of bolus administration of intravenous rhIL-15 in adults with refractory metastatic malignant melanoma and metastatic renal cell cancer. Five of 18 patients manifested a decrease in marker lesions, with 2 having clearing of lung lesions. A collaborative trial with the Cancer Immunotherapy Network (CITN) of subcutaneous Escherichia coli rhIL-15 has been completed where the MTD was 3 mcg/kg/day. Nineteen patients were enrolled at escalating doses with a profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8 T-cells with a maximal 3-fold expansion. An additional trial with continuous intravenous infusion of IL-15 had an MTD of 2 mcg/kg/day. Following the termination of CIV administration there was a 30-fold increase in the number of circulating NK cells and an over 350-fold increase in the number of CD56bright NK cells that were shown to be quite effective at antibody-dependent cellular cytotoxicity (ADCC), NKG2D/MIC and natural cytotoxicity. A particular challenge with rhIL-15 is that there is low-level expression of IL-15R alpha on antigen-presenting cells including DCs. To address this issue, IL-15 and IL-15R alpha combination is being evaluated in a clinical trial. A major conclusion is that for IL-15 and its capacity to activate NK cells, a very attractive antitumor strategy is to use IL-15 in conjunction with antitumor monoclonal antibodies to augment their ADCC. In one syngeneic model EL4 leukemic cells were transfected with human CD20 and administered intravenously to immunologically intact mice. Mice treated with either IL-15 or rituximab (anti-CD20) alone showed modest efficacy. This efficacy was markedly augmented when the two agents were administered together. In a second xenograft model, SCID/NOD mice bearing MET-1 ATL leukemia receiving either alemtuzumab (CAMPATH) or IL-15 alone had only modest efficacy that was markedly augmented by the combination of IL-15 plus alemtuzumab. This efficacy was lost in FcR gamma deleted mice supporting the hypothesis that its efficacy was due to ADCC. In additional studies, we demonstrated that both NK cells and macrophages are needed for optimal tumor clearance mediated by the combination of IL-15 and rituximab. In a working model of innate recognition, NK cells were induced by IL-15 to express NKG2D and FcrgamaIV and macrophages to express the partner Rea-1 during antitumor immune responses, thus IL-15 activated macrophages license NK cells to perform ADCC. These observations have been translated by the initiation of a clinical trial involving alemtuzumab plus IL-15 for patients with ATL. A trial is being initiated in patients with refractory and relapsed CLL with obinutuzumab plus IL-15. In addition to translate preclinical studies, a trial is being initiated using IL-15 in combination with anti-CTLA-4 and anti-PD-L1. Furthermore, to translate the observation of increase in activated CD8 T-cells, the combination of IL-15 with an agonistic anti-CD40 monoclonal antibody has shown augmented tumor antigen specific CD8 T-cells and increased tumor efficacy. Sckisel and coworkers demonstrated that the administration of a gamma cytokine (e.g., IL-15) leads to paralysis of CD4 but not CD8 T-cells that was mediated through transient exp |