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Abstract
IL-15 is a 14–15 kDa member of the four α-helix bundle of cytokines that acts through a heterotrimeric receptor involving IL-2/IL-15R β, γc and the IL-15 specific receptor subunit IL-15R α. IL-15 stimulates the proliferation of T, B and NK cells, and induces stem, central and effector memory CD8 T cells. In rhesus macaques, continuous infusion of recombinant human IL-15 at 20 μg/kg/day was associated with approximately a 10-fold increase in the numbers of circulating NK, γ/δ cells and monocytes, and an 80- to 100-fold increase in the numbers of effector memory CD8 T cells. IL-15 has shown efficacy in murine models of malignancy. Clinical trials involving recombinant human IL-15 given by bolus infusions have been completed and by subcutaneous and continuous intravenous infusions are underway in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL-15 with IL-15R α+/- IgFc.
Financial & competing interests disclosure
This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
IL-15 is a member of the four α-helix bundle family of cytokines. The IL-15 heterotrimeric receptor includes IL-2/IL-15R β shared with IL-2, γc shared with IL-2, IL-4, IL-7, IL-9, IL-21 and a private IL-15 receptor, IL-15R α.
As part of an immunological synapse, on the surface of dendritic cells, IL-15R α presents IL-15 in trans to NK and memory CD8 T cells that bear the other two IL-15 receptor subunits.
IL-15 can also function on cells that express the three cell elements of the IL-15 receptor in cis.
IL-15 augments proliferation of T, B and NK cells and induces the expression of stem, central and effector memory CD8 T cells.
IL-15 given by continuous intravenous infusion at 20 μg/kg/day to rhesus macaques was associated with an approximately 10-fold increase in the number of circulating NK cells and an 80- to 100-fold increase in the number of circulating effector memory CD8 T cells.
A clinical trial of daily bolus infusions of recombinant human IL-15 for 12 days has been completed with acceptable toxicity in 18 patients with metastatic malignant melanoma and metastatic renal cell cancer. The maximum tolerated dose in this bolus infusion study was 0.3 μg/kg/day for 12 days.
Phase I dose-escalation clinical trials with different dosing strategies that involve either subcutaneous or with continuous intravenous infusion of IL-15 have been initiated.
Clinical trials are being initiated with IL-15 + IL-15R α or IL-15 + IL-15R α IgFc.
Future trials are planned combining IL-15 with an agonistic anti-CD40 monoclonal antibody given to induce IL-15R α and to reverse the ‘helpless’ state of CD8 T cells.
Subsequent trials will involve IL-15 or IL-15/IL-15R α administered in association with anticancer monoclonal antibodies to augment antibody-dependent cellular toxicity.