New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus-tumor activity

// Cavan P. Bailey 1 , Tulin Budak-Alpdogan 3 , Christopher T. Sauter 1 , Michelle M. Panis 1 , Cihangir Buyukgoz 1 , Emily K. Jeng 2 , Hing C. Wong 2 , Neal Flomenberg 1 and Onder Alpdogan 1 1 Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 2 Altor BioScience Corporation, Miramar, FL, USA 3 Department of Hematology and Oncology, MD Anderson Cancer Center at Cooper, Camden, NJ, USA Correspondence to: Onder Alpdogan, email: onder.alpdogan@jefferson.edu Keywords: stem cell transplantation, interleukin-15, cytokine therapy, graft-versus-tumor activity, animal models Received: August 15, 2016 Accepted: April 28, 2017 Published: May 15, 2017 ABSTRACT Interleukin-15 (IL-15) is a potent cytokine that increases CD8 + T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 superagonist complex comprised of an IL-15N72D mutation and IL-15RαSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL-15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number of CD8 + T cells (specifically CD44 + memory/activated phenotype) and NK cells. Intracellular IFN-γ and TNF-α secretion by CD8 + T cells increased in the IL-15SA-treated group. IL-15SA also upregulated NKG2D expression on CD8 + T cells. Moreover, IL-15SA enhanced proliferation and cytokine secretion of adoptively transferred CFSE-labeled T cells in syngeneic and allogeneic models by specifically stimulating the slowly proliferative and nonproliferative cells into actively proliferating cells. We then evaluated IL-15SA’s effects on anti-tumor activity against murine mastocytoma (P815) and murine B cell lymphoma (A20). IL-15SA enhanced graft-versus-tumor (GVT) activity in these tumors following T cell infusion. Interestingly, IL-15 SA administration provided GVT activity against A20 lymphoma cells in the murine donor leukocyte infusion (DLI) model without increasing graft versus host disease. In conclusion, IL-15SA could be a highly potent T- cell lymphoid growth factor and novel immunotherapeutic agent to complement stem cell transplantation and adoptive immunotherapy.