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Stimulation of Natural Killer Cell-Mediated Tumor Immunity by an IL15/TGFβ-Neutralizing Fusion Protein. | LitMetric

Stimulation of Natural Killer Cell-Mediated Tumor Immunity by an IL15/TGFβ-Neutralizing Fusion Protein.

Cancer Res

Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, Georgia. Winship Cancer Institute, Emory University, Atlanta, Georgia. Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia.

Published: October 2016

AI Article Synopsis

  • * FIST15-treated NK and CD8 T cells showed significantly higher production of the antitumor cytokines IFNγ and TNFα compared to those treated with other combinations, resulting in effective lysis of TGFβ-overproducing melanoma cells at lower doses.
  • * In animal models, FIST15 not only prevented tumor establishment from engineered melanoma cells but also significantly improved responses in mice with existing tumors, demonstrating its potential as

Article Abstract

The clinical efficacy of immune cytokines used for cancer therapy is hampered by elements of the immunosuppressive tumor microenvironment such as TGFβ. Here we demonstrate that FIST15, a recombinant chimeric protein composed of the T-cell-stimulatory cytokine IL15, the sushi domain of IL15Rα and a TGFβ ligand trap, can overcome immunosuppressive TGFβ to effectively stimulate the proliferation and activation of natural killer (NK) and CD8 T cells with potent antitumor properties. FIST15-treated NK and CD8 T cells produced more IFNγ and TNFα compared with treatment with IL15 and a commercially available TGFβ receptor-Fc fusion protein (sTβRII) in the presence of TGFβ. Murine B16 melanoma cells, which overproduce TGFβ, were lysed by FIST15-treated NK cells in vitro at doses approximately 10-fold lower than NK cells treated with IL15 and sTβRII. Melanoma cells transduced to express FIST15 failed to establish tumors in vivo in immunocompetent murine hosts and could only form tumors in beige mice lacking NK cells. Mice injected with the same cells were also protected from subsequent challenge by unmodified B16 melanoma cells. Finally, mice with pre-established B16 melanoma tumors responded to FIST15 treatment more strongly compared with tumors treated with control cytokines. Taken together, our results offer a preclinical proof of concept for the use of FIST15 as a new class of biological therapeutics that can coordinately neutralize the effects of immunosuppressive TGFβ in the tumor microenvironment while empowering tumor immunity. Cancer Res; 76(19); 5683-95. ©2016 AACR.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050108PMC
http://dx.doi.org/10.1158/0008-5472.CAN-16-0386DOI Listing

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