Use of an oncolytic virus secreting GM-CSF as combined oncolytic and immunotherapy for treatment of colorectal and hepatic adenocarcinomas.
BACKGROUND
Oncolytic cancer therapy using herpes simplex viruses (HSV) that have direct tumoricidal effects and cancer immunotherapy using the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have each been effective in preclinical testing. NV1034 is a multimutated oncolytic HSV carrying the gene for murine GM-CSF that attempts to combine these 2 anticancer strategies. The purpose of this study was to compare NV1034 to NV1023, the parent HSV mutants lacking GM-CSF, to determine if such combined oncolytic and immunotherapy using a single vector has advantages over oncolytic therapy alone.


METHODS
Expression GM-CSF in vitro did not alter the infectivity, cytotoxicity, or replication of NV1034 compared to the noncytokine-secreting control. Tumors infected with NV1034 produced GM-CSF in picogram quantities. In vivo efficacy of the viruses against murine colorectal carcinoma CT26 and murine hepatoma Hepa l-6 was then tested in subcutaneous tumors in syngeneic Balb/c and C57 L/J mice, respectively. In these immune-competent models, NV1034 and NV1023 each demonstrated potent antitumor activity.


RESULTS
Treatment with NV1034 had significantly better antitumor effect compared to treatment with NV1023. Furthermore, there was no difference in the antitumor efficacy of these viruses in mice depleted of CD4+ and CD8+ T lymphocytes.


CONCLUSIONS
Viral vectors combining oncolytic and immunotherapy are promising agents in treatment of colorectal carcinoma and hepatoma.
Malhotra
Sandeep
S
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Kim
Teresa
T
Zager
Jonathan
J
Bennett
Joseph
J
Ebright
Michael
M
D'Angelica
Michael
M
Fong
Yuman
Y
D000230:Adenocarcinoma / Q000628:therapy*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D007167:Immunotherapy; D008113:Liver Neoplasms / Q000628:therapy*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000628:therapy; D050130:Oncolytic Virotherapy; D055502:Secondary Prevention; D018139:Simplexvirus / Q000235:genetics; D014779:Virus Replication
D016178:Granulocyte-Macrophage Colony-Stimulating Factor