title: Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma.
abstract: T cell checkpoint blockade with antibodies targeting programmed cell death (ligand)-1 (PD-1/PD-L1) and/or cytotoxic T lymphocyte-antigen 4 (CTLA-4) has improved therapy outcome in melanoma patients. However, a considerable proportion of patients does not benefit even from combined α-CTLA-4 and α-PD-1 therapy. We therefore examined to which extent T cell (co)stimulation and/or stereotactic body radiation therapy (SBRT) could further enhance the therapeutic efficacy of T cell checkpoint blockade in a genetically engineered mouse melanoma model that is driven by PTEN-deficiency, and BRAFV600 mutation, as in human, but lacks the sporadic UV-induced mutations. Tumor-bearing mice were treated with different combinations of immunomodulatory antibodies (α-CTLA-4, α-PD-1, α-CD137) or interleukin-2 (IL-2) alone or in combination with SBRT. None of our immunotherapeutic approaches (alone or in combination) had any anti-tumor efficacy, while SBRT alone delayed melanoma outgrowth. However, α-CD137 combined with α-PD-1 antibodies significantly enhanced the anti-tumor effect of SBRT, while the anti-tumor effect of SBRT was not enhanced by interleukin-2, or the combination of α-CTLA-4 and α-PD-1. We conclude that α-CD137 and α-PD-1 antibodies were most effective in enhancing SBRT-induced tumor growth delay in this mouse melanoma model, outperforming the ability of IL-2, or the combination of α-CTLA-4 and α-PD-1 to synergize with SBRT. Given the high mutational load and increased immunogenicity of human melanoma with the same genotype, our findings encourage testing α-CD137 and α-PD-1 alone or in combination with SBRT clinically, particularly in patients refractory to α-CTLA-4 and/or α-PD-1 therapy.
authors.affiliation: Divisions of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Paula
authors.initials: P
authors.lastname: Kroon
authors.affiliation: Divisions of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Jules
authors.initials: J
authors.lastname: Gadiot
authors.affiliation: Divisions of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Marlies
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Divisions of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Alessia
authors.initials: A
authors.lastname: Gasparini
authors.affiliation: Divisions of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Deken
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Divisions of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.affiliation: Divisions of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Jannie
authors.initials: J
authors.lastname: Borst
authors.affiliation: Divisions of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. c.blank@nki.nl.|Divisions of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl.
authors.forename: Christian U
authors.initials: CU
authors.lastname: Blank
authors.affiliation: Divisions of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. i.verbrugge@nki.nl.
authors.forename: Inge
authors.initials: I
authors.lastname: Verbrugge
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D003062:Codon; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects / Q000528:radiation effects; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015415:Biomarkers; D003062:Codon; D061026:Programmed Cell Death 1 Receptor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAFV600; CD137; Melanoma; PD-1; Radiotherapy; Stereotactic