Combining oncolytic HSV-1 with immunogenic cell death-inducing drug mitoxantrone breaks cancer immune tolerance and improves therapeutic efficacy.
Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has been validated in murine breast cancer models, oncolytic virus treatment alone is insufficient to break immune tolerance. Thus, we investigated enhancing efficacy through combination therapy with the immunogenic cell death-inducing chemotherapeutic drug, mitoxantrone. Despite a lack of enhanced cytotoxicity in vitro, HSV-1 ICP0 null oncolytic virus KM100 with 5 μmol/L mitoxantrone provided significant survival benefit to BALB/c mice bearing Her2/neu TUBO-derived tumors. This protection was mediated by increased intratumoral infiltration of neutrophils and tumor antigen-specific CD8(+) T cells. Depletion studies verified that CD8-, CD4-, and Ly6G-expressing cells are essential for enhanced efficacy of the combination therapy. Moreover, the addition of mitoxantrone to KM100 oncolytic virus treatment broke immune tolerance in BALB-neuT mice bearing TUBO-derived tumors. This study suggests that oncolytic viruses in combination with immunogenic cell death-inducing chemotherapeutics enhance the immunogenicity of the tumor-associated antigens, breaking immunologic tolerance established toward these antigens.
Authors' Affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Samuel T
ST
Workenhe
Jonathan G
JG
Pol
Brian D
BD
Lichty
Derek T
DT
Cummings
Karen L
KL
Mossman
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008942:Mitoxantrone / Q000494:pharmacology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology*; D012516:Osteosarcoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology
D000970:Antineoplastic Agents; D008942:Mitoxantrone; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human