Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms.
In this model of hepatic micrometastases, the antitumor efficacy and role of the T-cell and natural killer (NK) cell populations were studied for oncolytic herpes simplex virus type-1 (HSV-1) viral mutants containing the granulocyte-monocyte colony stimulating factor (GM-CSF (NV1034)) or interluken-12 (IL-12 (NV1042)) cytokine genes. These were compared to saline and control virus (NV1023) in vitro and in vivo. HSV-1 mutants were assessed for cytotoxicity, replication and cytokine expression in CT-26 cells. A syngeneic micrometastatic liver model was then established in naive and immune cell-depleted animals to assess the antitumor efficacy of these viruses. In vitro cytotoxicity and viral replication were similar for each virus, resulting in greater than 80 and 98% cytotoxicity at multiplicity of infection of 1 and 10, respectively. Peak viral titers were 25- to 50-fold higher than initial titer and were not significantly different between viruses. In vivo, all three viruses reduced metastases relative to control, but cytokine-secreting viruses did so with greater efficacy compared to NV1023. This effect was abrogated by T-cell depletion, but not NK-cell depletion. Single-agent therapy with oncolytic viral agents containing GM-CSF or IL-12 is effective in a murine model of liver metastases and likely involves direct viral oncolysis and actions of specific immune effector cells.
Derubertis
B G
BG
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Stiles
B M
BM
Bhargava
A
A
Gusani
N J
NJ
Hezel
M
M
D'Angelica
M
M
Fong
Y
Y
D000818:Animals; D018929:Cell Culture Techniques; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D008099:Liver; D051379:Mice; D023421:Models, Animal; D050130:Oncolytic Virotherapy; D018139:Simplexvirus / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D016207:Cytokines