title: Effective Combination of Innate and Adaptive Immunotherapeutic Approaches in a Mouse Melanoma Model.
abstract: Most cancer immunotherapies include activation of either innate or adaptive immune responses. We hypothesized that the combined activation of both innate and adaptive immunity will result in better antitumor efficacy. We have previously shown the synergy of an agonistic anti-CD40 mAb (anti-CD40) and CpG-oligodeoxynucleotides in activating macrophages to induce tumor cell killing in mice. Separately, we have shown that a direct intratumoral injection of immunocytokine (IC), an anti-GD2 Ab linked to IL-2, can activate T and NK cells resulting in antitumor effects. We hypothesized that activation of macrophages with anti-CD40/CpG, and NK cells with IC, would cause innate tumor destruction, leading to increased presentation of tumor Ags and adaptive T cell activation; the latter could be further augmented by anti-CTLA-4 Ab to achieve tumor eradication and immunological memory. Using the mouse GD2+B78 melanoma model, we show that anti-CD40/CpG treatment led to upregulation of T cell activation markers in draining lymph nodes. Anti-CD40/CpG + IC/anti-CTLA-4 synergistically induced regression of advanced s.c. tumors, resulting in cure of some mice and development of immunological memory against B78 and wild type B16 tumors. Although the antitumor effect of anti-CD40/CpG did not require T cells, the antitumor effect of IC/anti-CTLA-4 was dependent on T cells. The combined treatment with anti-CD40/CpG + IC/anti-CTLA-4 reduced T regulatory cells in the tumors and was effective against distant solid tumors and lung metastases. We suggest that a combination of anti-CD40/CpG and IC/anti-CTLA-4 should be developed for clinical testing as a potentially effective novel immunotherapy strategy.
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, WI 53705; rakhmil@humonc.wisc.edu.|Paul P. Carbone Comprehensive Cancer Center, Madison, WI 53705.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53705.
authors.forename: Mildred
authors.initials: M
authors.lastname: Felder
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, WI 53705.
authors.forename: Lauren
authors.identifier: 0000-0001-7346-4939
authors.initials: L
authors.lastname: Lever
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, WI 53705.
authors.forename: Jacob
authors.identifier: 0000-0002-0387-9976
authors.initials: J
authors.lastname: Slowinski
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, WI 53705.
authors.forename: Kayla
authors.initials: K
authors.lastname: Rasmussen
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, WI 53705.
authors.forename: Anna
authors.initials: A
authors.lastname: Hoefges
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, WI 53705.
authors.forename: Tyler J
authors.identifier: 0000-0003-2224-4017
authors.initials: TJ
authors.lastname: Van De Voort
authors.affiliation: Apeiron Biologics Inc., 1030 Vienna, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Loibner
authors.affiliation: Bristol-Myers Squibb Company, Redwood City, CA 94063.
authors.forename: Alan J
authors.identifier: 0000-0002-1142-8542
authors.initials: AJ
authors.lastname: Korman
authors.affiliation: Provenance Biopharmaceuticals, Carlisle, MA 01741; and.
authors.forename: Stephen D
authors.identifier: 0000-0002-2080-4220
authors.initials: SD
authors.lastname: Gillies
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, WI 53705.|Paul P. Carbone Comprehensive Cancer Center, Madison, WI 53705.|Department of Pediatrics, University of Wisconsin, Madison, WI 53705.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D007113:Immunity, Innate; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides