Combination vascular delivery of herpes simplex oncolytic viruses and amplicon mediated cytokine gene transfer is effective therapy for experimental liver cancer.
BACKGROUND
Herpes simplex type I (HSV)-based vectors have been used experimentally for suicide gene therapy, immunomodulatory gene delivery, and direct oncolytic therapy. The current study utilizes the novel concept of regional delivery of an oncolytic virus in combination with or serving as the helper virus for packaging herpes-based amplicon vectors carrying a cytokine transgene, with the goal of identifying if this combination is more efficacious than either modality alone.


METHODS
A replication competent oncolytic HSV (G207) and a replication incompetent HSV amplicon carrying the gene for the immunomodulatory cytokine IL-2 (HSV-IL2) were tested in murine syngeneic colorectal carcinoma and in rat hepatocellular carcinoma models. Liver tumors were treated with vascular delivery of (1) phosphate-buffered saline (PBS), (2) G207, (3) HSV-IL2, (4) G207 and HSV-IL2 mixed in combination (mG207/HSV- IL2), and (5) G207 as the helper virus for packaging the construct HSV-IL2 (pG207/HSV-IL2).


RESULTS
Tumor burden was significantly reduced in all treatment groups in both rats and mice treated with high-dose G207, HSV-IL2, or both (p < 0.02). When a low dose of virus was used in mice, anti-tumor efficacy was improved by use of G207 and HSV-IL2 in combination or with HSV-IL2 packaged by G207 (p < 0.001). This improvement was abolished when CD4(+) and CD8(+) lymphocytes were depleted, implying that the enhanced anti-tumor response to low-dose combined therapy is immune mediated.


CONCLUSIONS
Vascular regional delivery of oncolytic and amplicon HSV vectors can be used to induce improved anti-tumor efficacy by combining oncolytic and immunostimulatory strategies.
Zager
J S
JS
Department of Surgery, Hepatobiliary Division, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Delman
K A
KA
Malhotra
S
S
Ebright
M I
MI
Bennett
J J
JJ
Kates
T
T
Halterman
M
M
Federoff
H
H
Fong
Y
Y
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002470:Cell Survival; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000502:physiology*; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011897:Random Allocation; D051381:Rats; D011915:Rats, Inbred BUF; D014407:Tumor Cells, Cultured
D007376:Interleukin-2