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 | $1,117,366 | Project Dates | 01/01/2007 - 00/00/0000 |
Fiscal Year | 2015 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Bioengineering (100.0%) Cancer (100.0%) Metastasis (60.0%) |
Kidney Cancer (50.0%) Kidney Disease (50.0%) Melanoma (50.0%) Urinary System (50.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
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Abstract | |||
IL-15, that activates natural (NK) cells, has potential applications in cancer immunotherapy. Based on rhesus macaques' experiments, we performed a first-in-human Phase I dose-escalation trial of Escherichia coli (E. coli) produced rhIL-15 with NCI as the sponsor, Dr. Kevin Conlon as the Principal Investigator (PI) and Dr. Thomas Waldmann as Study Chairman and IND holder. This study was completed with 5 patients having finished their course of therapy at 3.0 mcg/kg/day, 4 patients having entered at 1.0 mcg/kg/day and 5 patients at the 0.3 mcg/kg/day dose of 12 daily infusions. Following the bolus IV infusion of IL-15 the serum concentrations of IL-15 at 10 minutes following infusion ranged from 20,000 to 90,000 picograms/mL-levels sufficient to signal through the IL-2/IL-15R beta and common gamma receptors shared with IL-2. The pharmacokinetics of various parameters for the 3.0, 1.0 and 0.3 mcg/kg/day doses resulted in a Cmax of 47,800 +/- 18,300 picograms/mL, 15,900 +/- 19,000 picograms/mL and 12,060 +/- 350 pg/mL respectively. The half-lives (T 1/2) were very similar for the three dose levels 2.4 +/- 0.5 hours, 2.7 +/- 0.13 hours and 2.7 +/- 0.67 hours. With a bolus infusion of 3.0 mcg/kg/day there was a pattern of fever beginning 2 to 2.5 hours following the start of the rhIL-15 infusions, peaking reliably at the 3-hour timepoint. Rigors occurred at the 4-hour timepoint. Rigors and fever were also observed at the 1.0 mcg/kg/day dose but were less severe. Up to 50-fold increases of serum levels of inflammatory cytokines in particular IL-6, IL-8 and IFN-gamma were observed. There was minimal fever observed at the 0.3 mcg/day dose. These toxicities were associated with maximum elevations at 4 to 8 hours post-bolus infusion of IL-15 in the serum concentrations of inflammatory cytokines (e.g. IL-16, IL-1, IL-8, IL-10 and IFN-gamma). Two patients manifested dose-limiting toxicity (DLT) at both the 3.0 mcg/kg/day (hypotension) and at the 1.0 mcg/kg/day (abnormalities of liver function). However the 0.3 mcg/kg/day dose has proven to be without DLT in the 5 patients examined. Flow cytometry of peripheral blood lymphocytes revealed a dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes upon IL-15 administration, followed by influx and hyperproliferation yielding10-fold expansions of NK and gamma delta T cells that ultimately returned to baseline. The pharmacokinetics of IL-15 following bolus infusion, discussed above, are clearly not optimal with exceedingly high levels initially that may have caused the toxicity. Therefore 2 additional clinical trials were initiated and are reaching completion using Escherichia coli rhIL-15 in the treatment of patients with metastatic malignancy. A trial was initiated using continuous intravenous infusion of rhIL-15 in the Clinical Center of the NCI. The maximum tolerated dose was 2 mcg/kg/day administered for a 10-day period. Furthermore, a subcutaneous dosing strategy was performed in concert with the Cancer Immunotherapy Network (CITN). In this dose-escalation trial 3 mcg/kg/day Monday-Friday for 2 weeks has been sustained without dose-limiting toxicity. In both the CITN subcutaneous trial and the continuous intravenous infusion in the one to three days following the termination of the IL-15 administration there was a dramatic increase that in the case of the CIV was 30-fold in the number of circulating NK cells and an over 200-fold increase in the number of CD56bright CD16dim NK-cell subpopulation. The approaches involving IL-15 studied to date were based on the hypothesis that the host is making an immune response albeit inadequate to the tumor and that this could be augmented by the administration of an IL-15 containing agent. However these cytokines could also be used in drug combination where an additional co-administered drug provides the specificity directed toward the tumor. In particular, IL-15 could be used with tumor-directed monoclonal antibodies to a |