Enhanced inhibition of syngeneic murine tumors by combinatorial therapy with genetically engineered HSV-1 expressing CCL2 and IL-12.
Herpes simplex viruses type 1 (HSV-1) that lack the gamma(1)34.5 gene are unable to replicate in the central nervous system (CNS), but maintain replication competence in actively dividing tumors. To determine if antitumor therapy by M002, a gamma(1)34.5(-) HSV that expresses interleukin-12 (IL-12), could be augmented by combinatorial therapy with another gamma(1)34.5-deleted HSV-1 engineered to express the chemokine CCL2, Neuro-2a tumors were established subcutaneously in the syngeneic A/J mouse strain. Tumors received multiple injections intratumorally either of saline, the parent, non-cytokine-expressing virus R3659, M002, M010 (gamma(1)34.5(-) HSV expressing CCL2), or a combination of M002 and M010. Efficacies were evaluated by monitoring inhibition of tumor growth over time. Results demonstrated the following: (1) inhibition of tumor growth was most pronounced in tumors treated with a combination of M002 and M010; (2) enhanced tumor growth inhibition for the combinatorial treatment group was statistically significant compared to either M002 or M010 alone; and (3) the variability between slopes of the tumor growth rates within an individual treatment group appeared to be virus-dependent, and was reproducible between experiments. Our results demonstrate that combinatorial cytokine/chemokine gamma(1)34.5(-) HSV therapies can provide superior antitumor effects in experimental tumors as a model for malignancies arising in the brain.
Parker
Jacqueline N
JN
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35294-3410, USA.
Meleth
Sreelatha
S
Hughes
Kenneth B
KB
Gillespie
G Yancey
GY
Whitley
Richard J
RJ
Markert
James M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics*; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005818:Genetic Engineering; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000235:genetics*; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy; D010957:Plasmids / Q000378:metabolism; D013997:Time Factors; D014709:Vero Cells
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D018932:Chemokine CCL2; D016207:Cytokines; D018664:Interleukin-12