title: Complete regression of advanced primary and metastatic mouse melanomas following combination chemoimmunotherapy.
abstract: The development of therapeutic strategies which induce effective cellular antitumor immunity represents an important goal in cancer immunology. Here, we used the unique features of the genetically engineered Hgf-Cdk4(R24C) mouse model to identify a combination chemoimmunotherapy for melanoma. These mice develop primary cutaneous melanomas which grow progressively and metastasize in the absence of immunogenic foreign proteins such as oncogenes or antigens. Primary and metastatic tumors evade innate and adaptive immune defenses, although they naturally express melanocytic antigens which can be recognized by antigen-specific T cells. We found that primary melanomas continued to grow despite infiltration with adoptively transferred, in vivo-activated, tumor-specific CD8(+) T cells. To promote tumor immune defense, we developed a treatment protocol consisting of four complementary components: (a) chemotherapeutic preconditioning prior to (b) adoptive lymphocyte transfer and (c) viral vaccination followed by (d) adjuvant peritumoral injections of immunostimulatory nucleic acids. Lymphocyte ablation and innate antiviral immune stimulation cooperatively enhanced the expansion and the effector cell differentiation of adoptively transferred lymphocytes. The efficacy of the different treatment approaches converged in the tumor microenvironment and induced a strong cytotoxic inflammatory response enabling preferential recognition and destruction of melanoma cells. This combination chemoimmunotherapy caused complete regression of advanced primary melanomas in the skin and metastases in the lung with minimal autoimmune side effects. Our results in a clinically highly relevant experimental model provide a scientific rationale to evaluate similar strategies which unleash the power of innate and adaptive immune defense in future clinical trials.
authors.affiliation: Department of Dermatology and Allergology, Laboratory of Experimental Dermatology, Institute of Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Kohlmeyer
authors.forename: Mira
authors.initials: M
authors.lastname: Cron
authors.forename: Jennifer
authors.initials: J
authors.lastname: Landsberg
authors.forename: Tobias
authors.initials: T
authors.lastname: Bald
authors.forename: Marcel
authors.initials: M
authors.lastname: Renn
authors.forename: Sandra
authors.initials: S
authors.lastname: Mikus
authors.forename: Sandra
authors.initials: S
authors.lastname: Bondong
authors.forename: Diana
authors.initials: D
authors.lastname: Wikasari
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016219:Immunotherapy, Adoptive; D007370:Interferon Type I / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009841:Oligonucleotides / Q000276:immunology / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D007370:Interferon Type I; D009841:Oligonucleotides; D011994:Recombinant Proteins; D003520:Cyclophosphamide; D011070:Poly I-C