orabase and Facial-Neoplasms

Devil facial tumor disease (DFTD) is renowned for its successful evasion of the host immune system. Down regulation of the major histocompatabilty complex class I molecule (MHC-I) on the DFTD cells is a primary mechanism of immune escape. Immunization trials on captive Tasmanian devils have previously demonstrated that an immune response against DFTD can be induced, and that immune-mediated tumor regression can occur. However, these trials were limited by their small sample sizes. Here, we describe the results of two DFTD immunization trials on cohorts of devils prior to their wild release as part of the Tasmanian Government's Wild Devil Recovery project. 95% of the devils developed anti-DFTD antibody responses. Given the relatively large sample sizes of the trials (

Topics: Adjuvants, Immunologic; Animals; Cancer Vaccines; Carboxymethylcellulose Sodium; Facial Neoplasms; Female; Histocompatibility Antigens Class I; Imiquimod; Immunity, Humoral; Immunization, Secondary; Immunoglobulin G; Immunotherapy; Male; Marsupialia; Poly I-C; Polylysine; Tumor Escape

Devil facial tumour disease (DFTD) describes two genetically distinct transmissible tumours that pose a significant threat to the survival of the Tasmanian devil. A prophylactic vaccine could protect devils from DFTD transmission. For this vaccine to be effective, potent immune adjuvants will be required. Toll-like receptors (TLRs) promote robust immune responses in human cancer studies and are highly conserved across mammalian species. In this study, we investigated the proficiency of TLR ligands for immune activation in the Tasmanian devil using in vitro mononuclear cell stimulations and in vivo immunisation trials with a model antigen. We identified two such TLR ligands, polyICLC (Hiltonol

Topics: Adjuvants, Immunologic; Aminoquinolines; Animals; Antigens; Cancer Vaccines; Carboxymethylcellulose Sodium; Cells, Cultured; Facial Neoplasms; Hemocyanins; Humans; Imiquimod; Immunity; Immunity, Innate; Immunization; Immunoglobulin G; Leukocytes, Mononuclear; Lymphocyte Activation; Marsupialia; Poly I-C; Polylysine; Toll-Like Receptors

Pathogen-associated molecular patterns (PAMP) are stand-alone innate and adaptive immunomodulators and critical vaccine components. We present a strategy of sequential intratumoral (i.t.) and intramuscular (i.m.) injections of the stabilized dsRNA viral mimic and PAMP, polyinosinic-polycytidylic acid-polylysine-carboxymethylcellulose (poly-ICLC, Hiltonol; Oncovir). We report the first treated patient, a young man with an exceptionally advanced facial embryonal rhabdomyosarcoma with extension to the brain. After treatment, the patient showed tumor inflammation consistent with immunotherapy, followed by gradual, marked tumor regression, with extended survival. Sequential i.t. and i.m. poly-ICLC injections mimicking a viral infection can induce an effective, in situ, personalized systemic therapeutic "autovaccination" against tumor antigens of a patient. We postulate a three-step immunomodulatory process: (i) innate-immune local tumor killing induced by i.t. poly-ICLC; (ii) activation of dendritic cells with Th1 cell- and CTL-weighted priming against the released tumor antigens; and (iii) i.m. poly-ICLC maintenance of the systemic antitumor immune response via chemokine induction, facilitation of CTL killing through the induction of costimulators such as OX40, inflammasome activation, and increase in the T-effector/Treg ratio. These results support the use of certain simple and inexpensive i.t. PAMPs to favorably stimulate effective immunity against solid cancers. A phase II clinical trial testing the hypothesis presented has begun accrual (clinicaltrials.gov, NCT01984892).

Topics: Adolescent; Brain Neoplasms; Cancer Vaccines; Carboxymethylcellulose Sodium; Drug Administration Routes; Facial Neoplasms; Humans; Immunologic Factors; Male; Poly I-C; Polylysine; Rhabdomyosarcoma, Embryonal; RNA, Double-Stranded; Vaccination