Recombinant Interleukin-15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in People With Refractory Cancers

IL-15 is a stimulatory cytokine that activates the immune system, inducing proliferation of T lymphocytes and NK cells. Administration of recombinant human IL-15 (rhIL-15) has been shown to result in a dramatic increase of circulating CD8+T cells and NK cells; these changes in immune cell populations suggest potential for anti-tumor activity.

Ipilimumab is a fully human monoclonal antibody against CTLA-4, a receptor present on the surface of activated T cells that functions as an immune checkpoint. Immune checkpoints pathways typically act to downregulate T cell activity and are co-opted by tumors to allow the malignant cells to evade the immune response. Blocking the engagement of CTLA-4 with ipilimumab allows infiltrating T cells to mount an anti-tumor response. Ipilimumab is approved by the FDA for the treatment of certain patients with melanoma and has shown clinical activity in other tumor types as well.

Nivolumab is a humanized monoclonal antibody against programmed death 1 (PD-1), a receptor present on the surface of activated T cells that functions as an immune checkpoint. One of the ligands for PD-1, PD-L1, is commonly expressed by tumor cells. Similar to inhibition of the CTLA-4 pathway by ipilimumab, blocking of PD-1/PD-L1 signaling by nivolumab allows infiltrating T cells to mount an an immune response against the tumor. Nivolumab is approved as a single agent for several cancer types, as well as for the treatment of advanced melanoma in combination with ipilimumab.