Posted May 16, 2019

Maureen Su, M.D., University of North Carolina-Chapel Hill

Immune checkpoint blockade, such as anti-CTLA-4 or anti-PD1, works by targeting T cells in the peripheral blood to activate anti-tumor immune functions. For patients with metastatic melanoma, treatment with immune checkpoint inhibitors has been successful in significantly extending overall survival; however, not every patient responds to this type of immunotherapy. Therefore, it is necessary to develop other therapies to improve the response of immune checkpoint inhibitors or alternative therapies for patients who do not respond. One potential strategy is to develop drugs that target central tolerance of the immune system. In the thymus, central tolerance is the process of deleting developing T cells that would react against the body’s own cells. Central tolerance helps prevent autoimmunity but also limits the production of T cells that recognize and target melanoma cells.

Maureen Su, with a FY14 Career Development Award, investigated whether blocking central tolerance in the thymus would enhance the effects of immune checkpoint blockade in treating melanoma. A key mediator of central tolerance is the gene autoimmune regulator (Aire). Dr. Su identified that a subset of thymic cells called medullary thymic epithelial cells (mTECs) express RANKL which, when stimulated, activates Aire and leads to the deletion of self-reactive T cells. An antibody against RANKL blocks Aire expression and decreases the frequency of mTECs, therefore increasing activation of T cells that could potentially target melanoma. Denosumab is an FDA-approved antibody therapeutic that targets RANKL. Dr. Su used this drug to determine if inhibiting RANKL in combination with immune checkpoint inhibitors is effective in treating melanoma. In mouse models of melanoma, denosumab has a synergistic effect with checkpoint inhibitors anti-CTLA4 and anti-PD1 and significantly decreased tumor growth and prolonged survival. These results were published in the Journal of Clinical Investigation in 2017.¹

The results of this project informed the development of a Phase II clinical trial for Stage III/IV melanoma patients in which denosumab will be used in combination with anti-PD1 immunotherapy. As of April 2019, the trial is recruiting patients at University of North Carolina Lineberger Comprehensive Cancer Center. Patients will be treated with either denosumab alone or in combination with anti-PD1 to determine if denosumab has an antitumor effect by increasing the number of tumor infiltrating T cells.²

 

References:

¹ Bakhru P, Zhu ML, Wang HH, et al. 2017. Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity. JCI Insight. 2(18):e93265.

² NCT03620019. Denosumab + Pembrolizumab in Patients with Stage IV Melanoma. https://clinicaltrials.gov/ct2/show/NCT03620019

Link:

Public and Technical Abstracts:  Central Tolerance Blockade to Augment Checkpoint Immunotherapy in Melanoma

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