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Central Tolerance Blockade to Augment Checkpoint Immunotherapy in Melanoma

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The University of North Carolina at Chapel Hill Chapel Hill United States

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We recently found that a new agent anti-RANKL antibody rescues melanoma-fighting T cells from thymus elimination.Anti-RANKL antibody is different from other cancer immunotherapies because of this unique mode of action. By itself, anti-RANKL antibody improves the survival of mice injected with melanoma cells. Because anti-RANKL antibody andcheckpoint inhibitors work in distinct, non-redundant ways, we hypothesize that anti-RANKL antibody will increasethe effectiveness of checkpoint inhibitors in rejecting melanoma tumors in mice and humans. This grant proposal willprovide critical information needed to bring anti-RANKL antibody to the clinic for treating advanced melanoma patients. To date, our findings include RANKL is expressed at high levels on human thymocytes RANK is expressed at higher levels in medullary thymic epithelial cells mTECs than in cortical thymic epithelial cells cTECs, addition of anti-RANKL antibody to human thymus cell culture decreases mTEC frequency, and addition of recombinant RANKL increases expression of mTECspecific Autoimmune Regulator Aire gene. In mice, antiRANKL antibody and checkpoint inhibition have additive effects in increasing survival in response to melanoma challenge. These findings lend preclinical evidence for using anti-RANKL antibody to block central tolerance in the clinical setting.

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Technical Report,15 Aug 2016,14 Aug 2017



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Approved For Public Release;

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