Insights gained in fundamental research have led to the development of immunological approaches for the prevention of infectious diseases and neoplasia, and for the treatment of patients with malignancy. Cytokines, including interleukin-2 (IL-2) and interleukin-15 (IL-15), play pivotal roles in controlling the proliferation and differentiation of the diverse cells of the immune system. IL-15 is a 14-15 kDa cytokine of the 4-alpha helix bundle family of cytokines (cover image). Interleukin-15 interacts with a heterotrimeric receptor that includes the private IL-15R alpha subunit, the IL-2/IL-15R beta subunit shared with IL-2, and the common gamma chain (γc) shared with IL-2 and other cytokines. Because of this sharing of cytokine receptors, IL-2 and IL-15 share roles in the maintenance and activation of natural killer (NK) and CD8+ regulatory T-cells. However, they also have contrasting roles in adaptive immune responses. The unique role of IL-2 is in the elimination of self-reactive T cells to prevent autoimmunity. IL-15 in contrast prolongs the survival of memory CD8+ T-cell responses to invading pathogens. IL-2 is a secreted cytokine that acts on its heterotrimeric receptor expressed on activated T cells. In contrast, IL-15 functions as a membrane-bound cytokine that acts in the context of cell-cell contact at an immunological synapse. Monocytes or dendritic cells activated with interferons, Toll-like receptors, or through ligation of CD40+ induce the coordinate expression of IL-15 and IL-15R alpha. The IL-15, linked to IL-15R alpha receptors expressed by monocyte or dendritic cells, recycles through endosomal vesicles leading to the persistence of membrane-bound IL-15R alpha and its associated IL-15 on the activated monocyte. IL-15R alpha presents IL-15 in trans to target NK and CD8+ memory T cells (cover image).

IL-2 has been approved for use by the U.S. Food and Drug Administration in the treatment of patients with metastatic renal cell cancer or metastatic malignant melanoma. However, IL-2 is not optimal because its administration is associated with the capillary leak syndrome, and its action is limited by its role in activation-induced cell death (AICD) and in the maintenance and fi tness of CD4+, CD25+ regulatory T cells that are negative checkpoints on the immune system. IL-15 is not involved in these checkpoints but rather in the generation and maintenance of NK, NK T cells, and memory CD8+ T cells. In light of these functional differences between the two cytokines in the life and death of lymphocytes, IL-15 may be superior to IL-2 in the therapy of cancer and as a component of molecular vaccines. In particular, IL-15 prolonged the survival of mice bearing syngeneic tumors in four models.

In light of the valuable immunological actions of IL-15 and its efficacy in preclinical models of neoplasia, the Waldmann Laboratory and the Biopharmaceutical Development Program (BDP) of the NCI, NIH, collaborated in the production of recombinant human IL-15. A phase I study of intravenous recombinant human IL-15 is being initiated for use in adults with refractory metastatic malignant melanoma and metastatic renal cell cancer, malignancies where IL-2 has been shown to be of value.

Cover Images: The structure of IL-15; A model of IL-15 receptor alpha chain (IL-15Rα) presentation of IL-15 in trans to neighboring NK and CD8+ T cells.

References:
  1. Waldmann TA, et al. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 2001;14:105-10.
  2. Dubois S, et al. IL-15R alpha recycles and presents IL-15 in trans to neighboring cells. Immunity 2002;17:537-47.
  3. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol. 2006;6:595-601.
  4. Sato N, Patel HJ, Waldmann TA, and Tagaya Y. The IL-15/IL-15 R alpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc. Natl. Acad. Sci. USA 2007;104:588-93.
  5. Zhang ML, et al. Interleukin-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancer. Proc. Nat. Acad. Sci. USA 2009;106:7513-8.



Download 2008 DEA Annual Report