First-in-Human Study of Interleukin-15 as Immunotherapy for Metastatic Cancer
Structure of the IL-15 molecule
One of the hallmarks of cancer that is now more clearly recognized is tumors’ ability to avoid recognition and destruction by the immune system. A novel class of treatments, dubbed immunotherapy, attempts to overcome this aspect by stimulating the immune system to attack cancer cells. The cytokine interleukin-2 (IL-2), which is approved for the treatment of renal cancer and melanoma, is the prototypic immunotherapy. Treatment with IL-2 enhances the proliferation of effector immune cells, such as cytotoxic T lymphocytes and natural killer (NK) cells. Unfortunately, IL-2 also exerts immunosuppressive activity through maintenance of regulatory T cells and activation-induced cell death. The related cytokine, interleukin-15 (IL-15), displays similar immune cell stimulatory activity, but without the inhibitory effects of IL-2. These findings, suggest that IL-15 may have greater potential as an immunotherapeutic agent and is consistent with the results seen in melanoma and prostate and colon cancer mouse models.
Based on extensive data generated in the laboratory of Thomas Waldmann, M.D., Co-Chief of CCR’s Lymphoid Malignancies Branch (LYMB), NCI’s Biological Resources Branch used a (E. coli) bacteria-based process to generate clinical-grade, recombinant, human IL-15 (rhIL-15) for use in humans. Toxicology testing in rhesus macaques revealed a four- to eight-fold increase in the numbers of circulating NK and CD8 T cells. After characterizing the safety and activity of rhIL-15 in the primate model, Waldmann, Kevin Conlon, M.D., also of LYMB, and their colleagues initiated a first-in-human (FIH) phase I study of rhIL-15 administered intravenously for 12 days to patients with metastatic malignant melanoma or renal cell cancer. The objectives of the trial were to determine the safety, adverse event profile, dose-limiting toxicity, and maximum tolerated dose. The initial study was designed to test escalating doses of rhIL-15. However, because two of the first patients treated with 3.0 μg/kg per day of rhIL-15 experienced dose-limiting toxicities, lower doses of 1.0 and 0.3 μg/kg per day were added. Five, four, and nine patients received intravenous infusions of 3.0, 1.0, and 0.3 μg/kg per day of rhIL-15, respectively.
Administration of rhIL-15 produced some unexpected changes in lymphocyte homeostasis in the blood so that within 20 minutes of the start of the infusions, the investigators observed a rapid reduction in circulating lymphocytes, most notably in NK and CD8 memory T cells. Appreciable proliferation and some movement of the NK cells back into circulation were seen in the first 24 hours after initiation of the treatment. NK cell numbers slowly normalized over the next two to three days that continued into hyperproliferation, ultimately producing a tenfold increase in circulating NK cells. In general, it took about six weeks for NK cell levels to return to normal and was accompanied by a short period of hypoproliferation. CD8 T cells showed a similar dynamic with less dramatic increases, however, γδ T cell numbers expanded similarly to that seen in NK cells. The increases were, for the most, part proportional to the dose of rhIL-15.
Pharmacokinetic results demonstrated similar half-lives of rhIL-15 of approximately 2.5 hours for the three dose levels with generally rapid declines in the maximum concentration, which was > 40,000pg/mL for the 3 µg/kg patients. Dose-limiting toxicities of the treatment included thrombocytopenia and hypotension in two patients treated with 3.0 μg/kg per day of rhIL-15 and liver enzyme elevations in two patients treated with 1.0 μg/kg per day of rhIL-15. Since none of the nine patients treated with the lowest dose experienced a dose-limiting toxicity, the researchers established 0.3 μg/kg per day of rhIL-15 as the maximum tolerated dose. Four patients even completed a second course of treatment at this dose. Other post-treatment adverse effects included fever, rigors or chills, and decreases in blood pressure, all common cytokine-related side effects. In contrast to treatment with IL-2, patients treated with rhIL-15 had only modest capillary leak syndrome. The time course of these side effects was predictable, and the effects were more severe with higher doses. Importantly, none of the patients developed antibodies to rhIL-15.
Interestingly, the cytokine-related side effects of decreased blood pressure, temperature spike and rigors coincided temporally with maximum post-treatment serum levels of interleukin-6 (IL-6) and interferon-γ. The investigators also observed a consistently high concentration of IL-6 receptor α and interleukin-8, which peaked somewhat later after resolution of the clinical side effects. Anticancer activity was assessed radiographically with computed tomography scans, and clinical responses determined using Response Evaluation Criteria in Solid Tumors (RECIST). The best response was stable disease, but five patients had tumor decreases of 10 to 30 percent, including two patients that had improvement and clearance of lung lesions.
The results of this early phase clinical trial indicate that rhIL-15 given as an intravenous bolus is safe at a low dose, but post-treatment side effects in the patients limited the ability to give the doses predicted by the nonhuman primate (NHP) toxicology experiments. However, treatment with rhIL-15 still induced appreciable changes in immune cell distribution, proliferation, and activation and suggested potential antitumor activity. Based on the results of this FIH trial and subsequent NHP toxicology experiments which showed greater immune activation and improved tolerability administering rhIL-15 as continuous intravenous infusion or subcutaneous injection, the LYMB has initiated clinical trials evaluating these alternative treatment regimens in patients with advanced metastatic cancers.Summary Posted: Mon, 12/01/2014
Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, Fleisher TA, Dubois SP, Perera LP, Stewart DM, Goldman CK, Bryant BR, Decker JM, Chen J, Worthy TA, Figg WD, Peer CJ, Sneller MC, Lane HC, Yovandich JL, Creekmore SP, Roederer M, and Waldmann TA. Redistribution, hyperproliferation, activation of natural killer and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human IL-15 in patients with cancer. J Clin Oncol. November 17, 2014 PubMed Link