Central Tolerance Blockade to Augment Checkpoint Immunotherapy in Melanoma
Abstract
Our preliminary data demonstrate that central tolerance blockade 1) expands the anti-melanoma immune response and 2) enhances the antimelanoma effects of immune checkpoint inhibition. Furthermore, we have identified anti-RANKL antibody as a pharmacologic agent that blocks central tolerance. Therefore, RANKL blockade is a promising therapy for enhancing checkpoint inhibitor efficacy in advanced melanoma. This observation has immediate clinical relevance given the FDA approval of anti-RANKL antibody for other indications, including bone metastases from cancer. In order to develop anti-RANKL antibody as a combination therapy with checkpoint inhibitors for advanced melanoma patients, several critical issues remain to be clarified and are the objectives of this grant proposal. These objectives are 1) to determine whether anti-RANKL-antibody similarly depletes Aire-expressing mTECs in the human thymus and 2) to determine whether central tolerance blockade with anti-RANKL and checkpoint inhibition will have additive effects in immune rejection of melanoma in mice. Based on our preliminary data, we hypothesize that combining anti-RANKL antibody and checkpoint inhibition will have additive effects on increasing the intratumoral ratio oF Teff:Treg cells and rejecting melanoma cells in mice and humans.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2018
- Accession Number
- AD1074218
Entities
People
- Maureen A Su