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Title
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Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma
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Author
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Abstract
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| 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 alpha-CTLA-4 and alpha-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 (alpha-CTLA-4, alpha-PD-1, alpha-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, alpha-CD137 combined with alpha-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 alpha-CTLA-4 and alpha-PD-1. We conclude that alpha-CD137 and alpha-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 alpha-CTLA-4 and alpha-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 alpha-CD137 and alpha-PD-1 alone or in combination with SBRT clinically, particularly in patients refractory to alpha-CTLA-4 and/or alpha-PD-1 therapy. |
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Language
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English
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Source (journal)
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Cancer immunology and immunotherapy. - Heidelberg
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Publication
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Heidelberg
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2016
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ISSN
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0340-7004
[print]
1432-0851
[online]
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DOI
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10.1007/S00262-016-1843-4
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Volume/pages
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65
:6
(2016)
, p. 753-763
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ISI
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000378872600010
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Pubmed ID
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27160390
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Full text (Publisher's DOI)
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