Article

Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation

Center for Research on Ovarian Cancer Early Detection and Cure, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cancer biology & therapy (Impact Factor: 3.63). 06/2008; 7(8):1194-205. DOI: 10.4161/cbt.7.8.6216
Source: PubMed

ABSTRACT We have previously shown that intratumor administration of HSV-1716 (an ICP34.5 null mutant) resulted in significant reduction of tumor growth and a significant survival advantage in a murine model of ovarian cancer. Herewith we report that oncolytic HSV-1716 generates vaccination effects in the same model. Upon HSV-1716 infection, mouse ovarian tumor cells showed high levels of expression viral glycoproteins B and D and were highly phagocyted by dendritic cells (DCs). Interestingly, increased phagocytosis of tumor-infected cells by DCs was impaired by heparin, and anti-HSV glycoproteins B and D, indicating that viral infection enhances adhesive interactions between DCs and tumor apoptotic bodies. Moreover, HSV-1716 infected cells expressed high levels of heat shock proteins 70 and GRP94, molecules that have been reported to induce maturation of DCs, increase cross-presentation of antigens and promote antitumor immune response. After phagocytosis of tumor-infected cells, DCs acquired a mature status in vitro and in vivo, upregulated the expression of costimulatory molecule and increased migration towards MIP-3beta. Furthermore, HSV-1716 oncolytic treatment markedly reduced vascular endothelial growth factor (VEGF) levels in tumor-bearing animals thus abrogating tumor immunosuppressive milieu. These mechanisms may account for the highly enhanced antitumoral immune responses observed in HSV-1716 treated animals. Oncolytic treatment induced a significantly higher frequency of tumor-reactive IFNgamma producing cells, and induced a robust tumor infiltration by T cells. These results indicate that oncolytic therapy with HSV-1716 facilitates antitumor immune responses.

0 Followers
 · 
161 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: To better understand melanoma resistance to herpes simplex virus type 1 (HSV-1)-mediated oncolysis, traditional two-dimensional (2D) cultures and extracellular matrix (ECM) containing three-dimensional (3D) cultures of OCM1 and C918 uveal melanoma cells were infected with an HSV-1 strain that expresses the green fluorescent protein (GFP) marker during replication. Although 2D cultures were completely destroyed within a few days of HSV-1 inoculation, viable GFP-negative tumor cells remained detectable in 3D cultures for several weeks. Tumor cells with increased resistance to HSV-1 included cells that formed vasculogenic mimicry patterns and multicellular spheroids and cells that invaded Matrigel individually. Mechanisms of tumor resistance against HSV-1 in the 3D environment included impaired virus spread in the ECM and ECM-mediated inhibition of viral replication after viral entry into tumor cells. Observations also suggested that HSV-1 established quiescent infection in some tumor cells present in multicellular spheroids and that this could revert to productive viral infection when the tumor growth pattern changed. These findings indicate that 3D tumor cell cultures can be used to identify distinct tumor cell populations with increased resistance to HSV-1 and to explore mechanisms of ECM-mediated tumor resistance to oncolytic virotherapy.
    Cancer gene therapy 11/2009; 17(4):223-34. DOI:10.1038/cgt.2009.73 · 2.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metastatic cancer remains an incurable disease in the majority of cases and thus novel treatment strategies such as oncolytic virotherapy are rapidly advancing toward clinical use. In order to be successful, it is likely that some type of combination therapy will be necessary to have a meaningful impact on this disease. Although it may be tempting to simply combine an oncolytic virus with the existing standard radiation or chemotherapeutics, the long-term goal of such treatments must be to have a rational, potentially synergistic combination strategy that can be safely and easily used in the clinical setting. The combination of oncolytic virotherapy with existing radiotherapy and chemotherapy modalities is reviewed along with novel biologic therapies including immunotherapies, in order to help investigators make intelligent decisions during the clinical development of these products.
    Molecular Therapy 12/2009; 18(2):251-63. DOI:10.1038/mt.2009.283 · 6.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although cancer vaccines with defined antigens are commonly used, the use of whole tumor cell preparations in tumor immunotherapy is a very promising approach and can obviate some important limitations in vaccine development. Whole tumor cells are a good source of TAAs and can induce simultaneous CTLs and CD4(+) T helper cell activation. We review current approaches to prepare whole tumor cell vaccines, including traditional methods of freeze-thaw lysates, tumor cells treated with ultraviolet irradiation, and RNA electroporation, along with more recent methods to increase tumor cell immunogenicity with HOCl oxidation or infection with replication-incompetent herpes simplex virus.
    Seminars in Immunology 03/2010; 22(3):132-43. DOI:10.1016/j.smim.2010.02.004 · 6.12 Impact Factor
Show more