Host lymphodepletion enhances the therapeutic activity of an oncolytic vaccinia virus expressing 4-1BB ligand.
Oncolytic viral vectors have shown promise as antitumor therapeutic agents but their effectiveness is complicated by induction of antiviral antibody responses and rapid host clearance of recombinant vectors. We developed a recombinant oncolytic vaccinia virus expressing the 4-1BBL T-cell costimulatory molecule (rV-4-1BBL) and showed modest tumor regression in the poorly immunogenic B16 murine melanoma model. To improve the therapeutic potential of this vector, we tested the antitumor activity of local intratumoral injection in the setting of host lymphodepletion, which has been shown to augment vaccination and adoptive T-cell therapy. In this model, rV-4-1BBL injection in the setting of lymphodepletion promoted MHC class I expression, reduced antiviral antibody titers, promoted viral persistence, and rescued effector-memory CD8(+) T cells, significantly improving the therapeutic effectiveness of the oncolytic vector. These data suggest that vaccination with rV-4-1BBL in the setting of host nonmyeloablative lymphodepletion represents a logical strategy for improving oncolytic vaccination in melanoma, and perhaps other cancers as well.
Kim
Hong Sung
HS
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York10029 =, USA.
Kim-Schulze
Seunghee
S
Kim
Dae Won
DW
Kaufman
Howard L
HL
D053330:4-1BB Ligand / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002478:Cells, Cultured; D005260:Female; D005805:Genes, MHC Class I; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics*; D014779:Virus Replication
D053330:4-1BB Ligand; D000914:Antibodies, Viral; D019496:Cancer Vaccines