Editors' ChoiceTransplantation

Can interleukin-15 keep its therapeutic promise?

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Science Translational Medicine  07 Mar 2018:
Vol. 10, Issue 431, eaar7532
DOI: 10.1126/scitranslmed.aar7532


The search continues for a therapeutic niche for interleukin-15 in human cancer treatment.

Interleukin (IL)–15 has been hailed as a promising immuno-oncology drug and was ranked the top potential immunotherapy agent by a National Cancer Institute workshop group over a decade ago. IL-15 is a member of the common gamma-chain cytokine family, and its receptor is expressed by hematopoietic cells, particularly T cells and natural killer (NK) cells. Basic research supports its role in T cell and NK cell homeostasis and its potential to drive T cell and NK cell antitumor responses. However, clinical trials of IL-15 in human solid tumors have not shown strong activity, and researchers have struggled to find a clinical role for the agent.

In a recent article, Romee et al. report a clinical trial of ALT-803, an IL-15–based superagonist, to treat patients with advanced hematological malignancies that relapsed after allogeneic stem cell transplantation. Because transplant recipients are populated with alloreactive donor lymphocytes that can mediate either graft-versus-leukemia (GVL) activity or graft-versus-host disease (GVHD), immunotherapy in this setting might be a double-edged sword. In the peripheral blood, ALT-803 increased NK cell proliferation and expansion and had more modest effects on T cells. Surprisingly it did not induce severe GVHD, suggesting that ALT-803 stimulation was insufficient to break graft T cell tolerance to host alloantigens. Two of 33 patients experienced clinical responses, with one a complete remission that lasted seven months.

This study demonstrates the safety and possibly an early signal of efficacy for an IL-15–based cancer treatment. It is informative that, with the dosing regimens in this study, the effect of IL-15 on T cells was relatively mild, with modest changes in peripheral blood CD8 T cells and an absence of severe GVHD. More effective IL-15–based immunotherapy may require combination with other agents, such as vaccines, checkpoint inhibitors, or adoptively transferred T cells. This study brings into focus the need to better understand the biology of IL-15 in humans and to apply this understanding to rational use of this agent for more effective treatments.

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