title: Combination immunotherapy for tumors via sequential intratumoral injections of oncolytic herpes simplex virus 1 and immature dendritic cells.
abstract: OBJECTIVE
  Oncolytic herpes simplex virus 1 (oHSV) vectors treat tumors in preclinical models and have been used safely in phase I clinical trials for patients with cancer. Infection of tumors with oHSV also induces specific antitumor immunity. We investigated whether this immunotherapeutic effect is enhanced by combining oHSV infection with intratumoral administration of immature myeloid dendritic cells (iDC).
  
  
  METHODS
  Subcutaneous neuroblastoma tumors were established in syngeneic immunocompetent mice and sequentially treated with oHSV(G47Delta) and intratumoral iDCs. Tumor volumes and survival were monitored. Antitumor immune responses were evaluated by immunohistochemistry, IFN-gamma ELISPOT, and CTL assay. Treatment was also evaluated in immunodeficient NOD-SCID mice.
  
  
  RESULTS
  We observed significant reductions in tumor volumes in mice receiving G47Delta + iDCs compared with those treated with G47Delta or iDC monotherapy. Survival was prolonged, with approximately 90% of tumors eradicated in the combination group. Combination therapy led to enhancement of antitumor immune responses, confirmed by increases in IFN-gamma expression by splenocytes harvested from G47Delta + iDC-treated mice. Splenocytes harvested from G47Delta + iDC-treated mice were effective against neuroblastoma tumor cells in a CTL assay. Immunohistochemistry of combination-treated tumors revealed robust lymphocytic infiltrates. Adding iDCs to G47Delta infection in tumors in NOD-SCID mice did not reduce the rate of growth. Substitution of lipopolysaccharide-matured dendritic cells abrogated the enhanced tumor volume reduction seen with combination therapy with iDCs.
  
  
  CONCLUSIONS
  Combination treatment of murine tumors with oHSV and iDCs reduces the volume of established tumors and prolongs survival via enhancement of antitumor immunity.
authors.affiliation: Brain Tumor Research Center, Simches Research Laboratories, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Farrell
authors.forename: Cecile
authors.initials: C
authors.lastname: Zaupa
authors.forename: Zachary
authors.initials: Z
authors.lastname: Barnard
authors.forename: Jason
authors.initials: J
authors.lastname: Maley
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martuza
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Rabkin
authors.forename: William T
authors.initials: WT
authors.lastname: Curry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D007371:Interferon-gamma