title: Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge.
abstract: Immune recognition of tumors can limit cancer development, but antitumor immune responses are often blocked by tumor-mediated immunosuppression. Because microbes or microbial constituents are powerful adjuvants to stimulate immune responses, we evaluated whether intratumoral administration of a highly immunogenic but attenuated parasite could induce rejection of an established poorly immunogenic tumor. We treated intradermal B16F10 murine melanoma by intratumoral injection of an attenuated strain of Toxoplasma gondii (cps) that cannot replicate in vivo and therefore is not infective. The cps treatment stimulated a strong CD8(+) T cell-mediated antitumor immune response in vivo that regressed established primary melanoma. The cps monotherapy rapidly modified the tumor microenvironment, halting tumor growth, and subsequently, as tumor-reactive T cells expanded, the tumors disappeared and rarely returned. The treatment required live cps that could invade cells and also required CD8(+) T cells and NK cells, but did not require CD4(+) T cells. Furthermore, we demonstrate that IL-12, IFN-γ, and the CXCR3-stimulating cytokines are required for full treatment efficacy. The treatment developed systemic antitumor immune activity as well as antitumor immune memory and therefore might have an impact against human metastatic disease. The approach is not specific for either B16F10 or melanoma. Direct intratumoral injection of cps has efficacy against an inducible genetic melanoma model and transplantable lung and ovarian tumors, demonstrating potential for broad clinical use. The combination of efficacy, systemic antitumor immune response, and complete attenuation with no observed host toxicity demonstrates the potential value of this novel cancer therapy.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Baird
authors.forename: Katelyn T
authors.initials: KT
authors.lastname: Byrne
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Lizotte
authors.forename: Seiko
authors.initials: S
authors.lastname: Toraya-Brown
authors.forename: Uciane K
authors.initials: UK
authors.lastname: Scarlett
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Alexander
authors.forename: Mee Rie
authors.initials: MR
authors.lastname: Sheen
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Fox
authors.forename: David J
authors.initials: DJ
authors.lastname: Bzik
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.forename: David W
authors.initials: DW
authors.lastname: Mullins
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Turk
authors.forename: Steven
authors.initials: S
authors.lastname: Fiering
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D045744:Cell Line, Tumor; D007271:Injections, Intradermal; D008546:Melanoma, Experimental / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000517:prevention & control; D012878:Skin Neoplasms / Q000276:immunology* / Q000517:prevention & control; D014122:Toxoplasma / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D014613:Vaccines, Attenuated