title: Therapeutic in situ autovaccination against solid cancers with intratumoral poly-ICLC: case report, hypothesis, and clinical trial.
abstract: 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).
authors.affiliation: Oncovir, Inc., Washington, District of Columbia; asalazar@starpower.net.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.affiliation: Bay Hematology-Oncology, Easton;
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Erlich
authors.affiliation: Bethesda MRI, Bethesda, Maryland; and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mark
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.affiliation: Oncovir, Inc., Washington, District of Columbia;
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Herberman
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004333:Drug Administration Routes; D005153:Facial Neoplasms / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008297:Male; D011070:Poly I-C / Q000627:therapeutic use*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012330:RNA, Double-Stranded; D018233:Rhabdomyosarcoma, Embryonal / Q000276:immunology / Q000628:therapy*; D014611:Vaccination / Q000379:methods
chemical_list: D019496:Cancer Vaccines; D007155:Immunologic Factors; D012330:RNA, Double-Stranded; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C