title: The addition of recombinant vaccinia HER2/neu to oncolytic vaccinia-GMCSF given into the tumor microenvironment overcomes MDSC-mediated immune escape and systemic anergy.
abstract: Effective immunotherapeutic strategies require the ability to generate a systemic antigen-specific response capable of impacting both primary and metastatic disease. We have built on our oncolytic vaccinia a granulocyte-macrophage colony-stimulating factor (GM-CSF) strategy by adding recombinant tumor antigen to increase the response in the tumor microenvironment and systemically. In the present study, orthotopic growth of a syngeneic HER2/neu-overexpressing mammary carcinoma in FVB/N mice (NBT1) was associated with increased Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs) both systemically and in the tumor microenvironment. This MDSC population had inhibitory effects on the HER2/neu-specific Th1 immune response. VVneu and VVGMCSF are recombinant oncolytic vaccinia viruses that encode HER2/neu and GM-CSF, respectively. Naive FVB mice vaccinated with combined VVneu and VVGMCSF given systemically developed systemic HER2/neu-specific immunity. NBT1-bearing mice became anergic to systemic immunization with combined VVneu and VVGMCSF. Intratumoral VVGMCSF failed to result in systemic antitumor immunity until combined with intratumoral VVneu. Infection/transfection of the tumor microenvironment with combined VVGMCSF and VVneu resulted in development of systemic tumor-specific immunity, reduction in splenic and tumor MDSC and therapeutic efficacy against tumors. These studies demonstrate the enhanced efficacy of oncolytic vaccinia virus recombinants encoding combined tumor antigen and GM-CSF in modulating the microenvironment of MDSC-rich tumors.
authors: Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
authors: C R
authors: CR
authors: de Vries
authors: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
authors: C E
authors: CE
authors: Monken
authors: Department of Surgery, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors: E C
authors: EC
authors: Lattime
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use; D045744:Cell Line, Tumor; D017635:Clonal Anergy; D005260:Female; D018734:Genes, erbB-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000502:physiology; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019139:Tumor Escape; D059016:Tumor Microenvironment / Q000276:immunology; D014611:Vaccination; D014616:Vaccinia virus / Q000235:genetics*
chemical_list: D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
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