Efficacy of multiagent herpes simplex virus amplicon-mediated immunotherapy as adjuvant treatment for experimental hepatic cancer.
OBJECTIVE
To evaluate the use of herpes simplex viral (HSV) amplicon vectors for production of tumor vaccines and to determine if such vaccines expressing combinations of immunostimulatory agents may be effective in the treatment of experimental liver cancer.


METHODS
A hepatic metastatic tumor model using CT-26 colorectal cancer in syngeneic Balb/C mice was utilized. Tumor vaccines were produced by brief (20 minutes) exposure of irradiated tumor cells to herpes amplicon vectors carrying the transgene for RANTES, B7.1, or GM-CSF. The antitumor efficacy of vaccination using tumor cells secreting GM-CSF (single agent) or a combination of RANTES/B7.1/GM-CSF (multiagent) was tested. The effect of 60% hepatectomy or T-cell depletion was also tested in this model.


RESULTS
In vitro assays confirmed high-level cytokine or costimulatory molecule production by cells transduced with amplicons. Antitumor efficacy was observed with single-agent or multiagent treatment. Without hepatectomy, immunization with single-agent or multiagent vaccine therapy appears equivalent. When administered in the setting of hepatectomy, multiagent regimens produced a higher cure rate than single-agent therapy (50% vs. 12.5%, =.03). Animals treated with GM-CSF alone had an average nodule count of 40 +/- 19 ( <.006 vs. Hep control 232 +/- 30), while animals treated with multiagent therapy had an average nodule count of 11 +/- 7 ( <.0004 vs. control). CD4 and CD8 lymphocyte blockade abrogated observed efficacy, confirming a lymphocyte-mediated response.


CONCLUSIONS
Tumor vaccines produced using HSV amplicon-mediated gene transfer may be useful in the treatment of liver malignancies. In the setting of hepatectomy, multiagent vaccine therapy offers an advantage over single-agent therapy. These data encourage consideration of such HSV-based neoadjuvant immunotherapy for treatment of liver malignancies.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Keith A
KA
Delman
Jonathan S
JS
Zager
Joseph J
JJ
Bennett
Sandeep
S
Malhotra
Michael I
MI
Ebright
Priscilla F
PF
McAuliffe
Marc W
MW
Halterman
Howard J
HJ
Federoff
Yuman
Y
Fong
D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D018946:Chemokine CCL5 / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006498:Hepatectomy; D006561:Herpes Simplex / Q000235:genetics*; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D014161:Transduction, Genetic / Q000379:methods*
D018122:B7-1 Antigen; D019496:Cancer Vaccines; D018946:Chemokine CCL5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor