Kayla E A Duval1,2, Robert J Wagner1, Veronique Beiss3, Steven N Fiering1,4, Nicole F Steinmetz3,5,6,7,8, P Jack Hoopes1,2,4. 1. Geisel School of Medicine, Dartmouth College, Hanover, NH, United States. 2. Thayer School of Engineering, Dartmouth College, Hanover, NH, United States. 3. Department of NanoEngineering, University of California San Diego, La Jolla, CA, United States. 4. Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States. 5. Department of Bioengineering, University of California San Diego, La Jolla, CA, United States. 6. Department of Radiology, University of California San Diego, La Jolla, CA, United States. 7. Moores Cancer Center, University of California San Diego, La Jolla, CA, United States. 8. Center for Nano-ImmunoEngineering, University of California San Diego, La Jolla, CA, United States.
Abstract
INTRODUCTION: Virus and virus-like nanoparticles (VNPs) have been used for a variety of preclinical treatments, including in situ anti-cancer vaccination. The Cowpea mosaic virus (CPMV) is a VNP that has shown the ability to stimulate an anti-cancer immune response. The hypothesis of this study is two-fold: that intratumoral CPMV enhances the immunogenetic and cytotoxic response of hypofractionated radiation (15 Gy or 3 x 8 Gy), and that the effect differs between fraction regimens in the murine B16 flank melanoma model. METHODS: CPMV nanoparticles were delivered intratumorally, 100 μg/tumor to B16 murine melanoma flank tumors alone, and in combination with either 15 Gy or 3 x 8 Gy (3 consecutive days). Tumors were assessed for immune and cytotoxic gene and protein expression, and cytotoxic T cell infiltration 4 days post treatment. Treatment based tumor control was assessed by a 3-fold tumor growth assay. RESULTS: Both CPMV and radiation alone demonstrated the activation of a number of important immune and cytotoxic genes including natural killer cell and T cell mediated cytotoxicity pathways. However, the combination treatment activated greater expression than either treatment alone. CPMV combined with a single dose of 15 Gy demonstrated greater immune and cytotoxic gene expression, protein expression, CD8+ T cell infiltration activity, and greater tumor growth delay compared to 3 x 8 Gy with CPMV. CONCLUSION: CPMV presents a unique and promising hypofractionated radiation adjuvant that leads to increased anti-tumor cytotoxic and immune signaling, especially with respect to the immune mediated cytotoxicity, immune signaling, and toll-like receptor signaling pathways. This improvement was greater with a single dose than with a fractionated dose.
INTRODUCTION: Virus and virus-like nanoparticles (VNPs) have been used for a variety of preclinical treatments, including in situ anti-cancer vaccination. The Cowpea mosaic virus (CPMV) is a VNP that has shown the ability to stimulate an anti-cancer immune response. The hypothesis of this study is two-fold: that intratumoral CPMV enhances the immunogenetic and cytotoxic response of hypofractionated radiation (15 Gy or 3 x 8 Gy), and that the effect differs between fraction regimens in the murine B16 flank melanoma model. METHODS: CPMV nanoparticles were delivered intratumorally, 100 μg/tumor to B16 murine melanoma flank tumors alone, and in combination with either 15 Gy or 3 x 8 Gy (3 consecutive days). Tumors were assessed for immune and cytotoxic gene and protein expression, and cytotoxic T cell infiltration 4 days post treatment. Treatment based tumor control was assessed by a 3-fold tumor growth assay. RESULTS: Both CPMV and radiation alone demonstrated the activation of a number of important immune and cytotoxic genes including natural killer cell and T cell mediated cytotoxicity pathways. However, the combination treatment activated greater expression than either treatment alone. CPMV combined with a single dose of 15 Gy demonstrated greater immune and cytotoxic gene expression, protein expression, CD8+ T cell infiltration activity, and greater tumor growth delay compared to 3 x 8 Gy with CPMV. CONCLUSION: CPMV presents a unique and promising hypofractionated radiation adjuvant that leads to increased anti-tumor cytotoxic and immune signaling, especially with respect to the immune mediated cytotoxicity, immune signaling, and toll-like receptor signaling pathways. This improvement was greater with a single dose than with a fractionated dose.
Authors: Julián Pardo; Alberto Bosque; Reina Brehm; Reinhard Wallich; Javier Naval; Arno Müllbacher; Alberto Anel; Markus M Simon Journal: J Cell Biol Date: 2004-11-08 Impact factor: 10.539
Authors: P H Lizotte; A M Wen; M R Sheen; J Fields; P Rojanasopondist; N F Steinmetz; S Fiering Journal: Nat Nanotechnol Date: 2015-12-21 Impact factor: 39.213