Oncotarget

Research Papers:

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

Cavan P. Bailey, Tulin Budak-Alpdogan, Christopher T. Sauter, Michelle M. Panis, Cihangir Buyukgoz, Emily K. Jeng, Hing C. Wong, Neal Flomenberg and Onder Alpdogan _

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Oncotarget. 2017; 8:44366-44378. https://doi.org/10.18632/oncotarget.17875

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Abstract

Cavan P. Bailey1, Tulin Budak-Alpdogan3, Christopher T. Sauter1, Michelle M. Panis1, Cihangir Buyukgoz1, Emily K. Jeng2, Hing C. Wong2, Neal Flomenberg1 and Onder Alpdogan1

1Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

2Altor BioScience Corporation, Miramar, FL, USA

3Department of Hematology and Oncology, MD Anderson Cancer Center at Cooper, Camden, NJ, USA

Correspondence to:

Onder Alpdogan, email: [email protected]

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.


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