title: Induction of protective immunity to RM-1 prostate cancer cells with ALVAC-IL-2/IL-12/TNF-alpha combination therapy.
abstract: Human prostate cancers characteristically express low levels of major histocompatibility complex (MHC) Class I, which makes it challenging to induce protective antitumor responses involving T cells. Here we demonstrate that a whole cell tumor vaccine can induce protective T cell immunity to a low MHC Class I-expressing mouse prostate cancer cell line, RM-1. ALVAC recombinant canarypox viruses encoding interleukin-2, interleukin-12 and tumor necrosis factor-alpha were used to create therapeutic vaccines in 2 different ways. The RM-1 cells were pre-infected in vitro with the viruses prior to injection (pre-infection vaccine) or the RM-1 cells were injected alone, followed by the viruses (separate injection vaccine). The vaccines were each tested subcutaneously or intradermally. The pre-infection vaccine resulted in 100% clearance of primary tumors, whereas intradermal delivery of the separate injection vaccine cleared 40-60% of primary tumors. Despite the highly efficient primary tumor clearance by the pre-infection vaccine, only the separate injection vaccine generated protection upon rechallenge. Tumor-free survival induced by the separate injection vaccine required natural killer (NK) cells, CD4(+), and CD8(+) T cells. None of these cells alone were sufficient to induce tumor-free survival to the primary challenge, demonstrating an important cooperativity between NK cells and T cells. Secondary clearance of tumors also required NK and CD8(+) T cells, but not CD4(+) T cells. We report for the first time the generation of T cell immunity to the RM-1 prostate cancer cell line, demonstrating that it is possible to generate protective T cell immunity to a MHC I-low expressing tumor.
authors.affiliation: Medical Scientist Training Program, University of Iowa, Iowa City, IA 52242-1089, USA.
authors.forename: Julieann F
authors.initials: JF
authors.lastname: Grant
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Iwasawa
authors.forename: Haley W
authors.initials: HW
authors.lastname: Sinn
authors.forename: D Robert
authors.initials: DR
authors.lastname: Siemens
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Griffith
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Takacs
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Ratliff
mesh_terms: D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: C078788:ALVAC vaccine; D014409:Tumor Necrosis Factor-alpha; D014765:Viral Vaccines; D018664:Interleukin-12