Potentiating cancer immunotherapy using an oncolytic virus.

Oncolytic viruses (OVs) are highly immunogenic and this limits their use in immune-competent hosts. Although immunosuppression may improve viral oncolysis, this gain is likely achieved at the cost of antitumoral immunity. We have developed a strategy wherein the immune response against the OV leads to enhanced therapeutic outcomes. We demonstrate that immunization with an adenoviral (Ad) vaccine before treatment with an oncolytic vesicular stomatitis virus (VSV) expressing the same tumor antigen (Ag) leads to significantly enhanced antitumoral immunity. Intratumoral replication of VSV was minimally attenuated in Ad-immunized hosts but extending the interval between treatments reduced the attenuating effect and further increased antitumoral immunity. More importantly, our combination approach shifted the immune response from viral Ags to tumor Ags and further reduced OV replication in normal tissues, leading to enhancements in both efficacy and safety. These studies also highlight the benefits of using a replicating, OV to boost a pre-existing antitumoral immune response as this approach generated larger responses versus tumor Ag in tumor-bearing hosts than could be achieved in tumor-free hosts. This strategy should be applicable to other vector combinations, tumor Ags, and tumor targets.

[1]  A. Fattaey,et al.  An Adenovirus Mutant That Replicates Selectively in p53- Deficient Human Tumor Cells , 1996, Science.

[2]  H. HogenEsch,et al.  Encapsulation of recombinant adenovirus into alginate microspheres circumvents vector-specific immune response , 2002, Gene Therapy.

[3]  R. Vile,et al.  Live attenuated measles virus induces regression of human lymphoma xenografts in immunodeficient mice. , 2001, Blood.

[4]  C. Chuang,et al.  Combination of Viral Oncolysis and Tumor-Specific Immunity to Control Established Tumors , 2009, Clinical Cancer Research.

[5]  R. Martuza,et al.  Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers , 2006, Cancer Gene Therapy.

[6]  E. Genden,et al.  Interleukin‐12 Expression Enhances Vesicular Stomatitis Virus Oncolytic Therapy in Murine Squamous Cell Carcinoma , 2007, The Laryngoscope.

[7]  M. Whitt,et al.  Recombinant vesicular stomatitis viruses from DNA. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Bramson,et al.  High-dose chemotherapy augments the efficacy of recombinant adenovirus vaccines and improves the therapeutic outcome , 2009, Cancer Gene Therapy.

[9]  K. Mossman,et al.  The role of ICP0-Null HSV-1 and interferon signaling defects in the effective treatment of breast adenocarcinoma. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[10]  D. Curiel,et al.  Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses , 2006, Molecular Cancer Therapeutics.

[11]  Laird Ak.  DYNAMICS OF TUMOR GROWTH. , 1964 .

[12]  B. Lichty,et al.  Heterologous Boosting of Recombinant Adenoviral Prime Immunization With a Novel Vesicular Stomatitis Virus–vectored Tuberculosis Vaccine , 2008, Molecular Therapy.

[13]  K. Ulbrich,et al.  Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies , 2001, Gene Therapy.

[14]  Ralph Weissleder,et al.  Cyclophosphamide increases transgene expression mediated by an oncolytic adenovirus in glioma-bearing mice monitored by bioluminescence imaging. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[15]  J. Bell,et al.  The p14 FAST Protein of Reptilian Reovirus Increases Vesicular Stomatitis Virus Neuropathogenesis , 2008, Journal of Virology.

[16]  J. Sham,et al.  Immune gene-viral therapy with triplex efficacy mediated by oncolytic adenovirus carrying an interferon-gamma gene yields efficient antitumor activity in immunodeficient and immunocompetent mice. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[17]  R. Martuza,et al.  Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity. , 1999, Human gene therapy.

[18]  H. Atkins,et al.  VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. , 2003, Cancer cell.

[19]  J. Fallon,et al.  Enhanced oncolytic potency of vesicular stomatitis virus through vector-mediated inhibition of NK and NKT cells , 2009, Cancer Gene Therapy.

[20]  Kah-Whye Peng,et al.  Viruses as anticancer drugs. , 2007, Trends in pharmacological sciences.

[21]  David L Woodland,et al.  Jump-starting the immune system: prime-boosting comes of age. , 2004, Trends in immunology.

[22]  M. L. Martins,et al.  A multiscale mathematical model for oncolytic virotherapy. , 2009, Cancer research.

[23]  Y. Tsutsumi,et al.  PEGylated adenovirus vectors containing RGD peptides on the tip of PEG show high transduction efficiency and antibody evasion ability , 2005, The journal of gene medicine.

[24]  A. García-Sastre,et al.  Recombinant Newcastle Disease Virus as a Vaccine Vector for Cancer Therapy , 2008, Molecular Therapy.

[25]  R. Vile,et al.  The oncolytic virotherapy treatment platform for cancer: Unique biological and biosafety points to consider , 2002, Cancer Gene Therapy.

[26]  S. Nishikawa,et al.  Reovirus as an oncolytic agent against experimental human malignant gliomas. , 2001, Journal of the National Cancer Institute.

[27]  T. Kubota,et al.  In situ cancer vaccination with a replication-conditional HSV for the treatment of liver metastasis of colon cancer , 2002, Cancer Gene Therapy.

[28]  L. Albritton,et al.  Jaagsiekte Sheep Retrovirus Utilizes a pH-Dependent Endocytosis Pathway for Entry , 2007, Journal of Virology.

[29]  A. García-Sastre,et al.  Use of reverse genetics to enhance the oncolytic properties of Newcastle disease virus. , 2007, Cancer research.

[30]  J. Fallon,et al.  Exponential enhancement of oncolytic vesicular stomatitis virus potency by vector-mediated suppression of inflammatory responses in vivo. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  S. Abrams,et al.  How tumours escape mass destruction , 2008, Oncogene.

[32]  R. Alemany,et al.  Tumor cells as cellular vehicles to deliver gene therapies to metastatic tumors , 2005, Cancer Gene Therapy.

[33]  Zihua Zeng,et al.  Coadministration of a herpes simplex virus-2 based oncolytic virus and cyclophosphamide produces a synergistic antitumor effect and enhances tumor-specific immune responses. , 2007, Cancer research.

[34]  P. Grambsch,et al.  Proportional hazards tests and diagnostics based on weighted residuals , 1994 .

[35]  P. Earl,et al.  Immunogenicity of viral vector, prime-boost SIV vaccine regimens in infant rhesus macaques: attenuated vesicular stomatitis virus (VSV) and modified vaccinia Ankara (MVA) recombinant SIV vaccines compared to live-attenuated SIV. , 2010, Vaccine.

[36]  J. Bramson,et al.  Vaccination-Induced Autoimmune Vitiligo Is a Consequence of Secondary Trauma to the Skin , 2004, Cancer Research.

[37]  J. Bramson,et al.  Elevated frequencies of self-reactive CD8+ T cells following immunization with a xenoantigen are due to the presence of a heteroclitic CD4+ T-cell helper epitope. , 2007, Cancer research.

[38]  B. Moss,et al.  gp100/pmel 17 Is a Murine Tumor Rejection Antigen: Induction of “Self”-reactive, Tumoricidal T Cells Using High-affinity, Altered Peptide Ligand , 1998, The Journal of experimental medicine.

[39]  J. Boudreau,et al.  Vesicular stomatitis virus as a novel cancer vaccine vector to prime antitumor immunity amenable to rapid boosting with adenovirus. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[40]  James M. Wilson,et al.  “Stealth” Adenoviruses Blunt Cell-Mediated and Humoral Immune Responses against the Virus and Allow for Significant Gene Expression upon Readministration in the Lung , 2001, Journal of Virology.

[41]  P. Fournier,et al.  Recombinant Newcastle disease virus expressing human interleukin-2 serves as a potential candidate for tumor therapy. , 2008, Virus research.

[42]  S. Russell,et al.  Infected cell carriers: a new strategy for systemic delivery of oncolytic measles viruses in cancer virotherapy. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[43]  H. Fukuhara,et al.  Triple gene-deleted oncolytic herpes simplex virus vector double-armed with interleukin 18 and soluble B7-1 constructed by bacterial artificial chromosome-mediated system. , 2005, Cancer research.

[44]  H. Atkins,et al.  Carrier cell-based delivery of an oncolytic virus circumvents antiviral immunity. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[45]  Xiaoliu Zhang,et al.  Induction of strong antitumor immunity by an HSV‐2‐based oncolytic virus in a murine mammary tumor model , 2007, The journal of gene medicine.

[46]  Yu Seong Lee,et al.  Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect , 2006, Gene Therapy.

[47]  Nahum Sonenberg,et al.  Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus , 2000, Nature Medicine.

[48]  Roberto Cattaneo,et al.  Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded , 2008, Nature Reviews Microbiology.

[49]  R. Vile,et al.  Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. , 2007, Cancer research.

[50]  F. Graham,et al.  Development of a FLP/frt system for generating helper-dependent adenoviral vectors. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.