Central Tolerance Blockade to Augment Checkpoint Immunotherapy in Melanoma

Principal Investigator: SU, MAUREEN A
Program: PRCRP
Proposal Number: CA140238
Award Number: W81XWH-15-1-0411
Funding Mechanism: Career Development Award
Partnering Awards:
Award Amount: $547,200.00


Scientific Objective and Rationale: Skin cancer is the most common form of cancer in the U.S. Although melanoma represents less than 5% of skin cancers, melanoma accounts for 75% of skin cancer deaths. If melanoma is detected early and has not spread to distant sites, melanomas are highly curable by surgical excision. However, if melanoma is detected late and has spread to distant sites, melanomas are rarely curable. Since 2011, the Food and Drug Administration (FDA) has approved two "checkpoint inhibitor" therapies (ipilimumab and pembrolizumab) for treatment of advanced melanoma. Unfortunately, however, most patients do not have a durable response to these treatments. We aim to increase the number of advanced melanoma patients who will benefit from therapy by increasing the effects of checkpoint inhibitor therapy.

Checkpoint inhibitors work by activating the immune system's T cells to fight melanoma, and we recently found that a major barrier limiting the effects of checkpoint inhibitors is the thymus gland. T cells mature within the thymus gland, and many melanoma-fighting T cells are specifically eliminated in the thymus before their maturation is complete. Although checkpoint inhibitors activate T cells after they have left the thymus, they do not protect developing melanoma-specific T cells within the thymus from elimination. We reasoned that preventing T cell elimination within the thymus would increase the number of melanoma-fighting T cells available for activation by checkpoint inhibitors and, ultimately, increase melanoma kill. Therapies directed at saving T cells from thymus elimination, however, have not previously been developed.

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 and checkpoint inhibitors work in distinct, non-redundant ways, we hypothesize that anti-RANKL antibody will increase the effectiveness of checkpoint inhibitors in rejecting melanoma tumors in mice and humans. This grant proposal will provide critical information needed to bring anti-RANKL antibody to the clinic for treating advanced melanoma patients.

Principal Investigator Career Goals in Cancer Research: I am a physician scientist who has expertise in how T cells develop within the thymus organ. We recently discovered that while preventing autoimmunity, the thymus also eliminates many melanoma-fighting T cells. Because this finding could be critical to improving melanoma immunotherapy, my career goals have evolved to developing ways to block elimination of melanoma-fighting T cells in the thymus to improve melanoma immunotherapy (Fiscal Year 2014 Peer Reviewed Cancer Research Program Topic Area). I believe that this grant will be key in helping me to make this critical career transition into cancer research. This grant will provide the protected time and cancer research mentorship that I will require to develop anti-RANKL antibody as a melanoma immunotherapy.

Ultimate Applicability of the Research: An estimated 9,000 Americans will still die from melanoma in 2014. Improving the effectiveness of advanced melanoma therapy is therefore an important public health priority. In this grant, we will develop a new agent, anti-RANKL antibody, that has the potential to improve the effectiveness of checkpoint inhibition therapy in advanced melanoma patients. Because anti-RANKL antibody is already FDA approved for other indications, we anticipate rapid translation of this therapy to clinical testing in advanced melanoma patients. Additionally, we will exploit the resources and expertise available in University of North Carolina's Lineberger Comprehensive Cancer Center to translate our findings to the clinical realm. Thus, this research has the potential to benefit advanced melanoma patients in the next 5 years.

Benefit to Active Duty Service Members, Their Families, and Other Military Beneficiaries: Sun exposure is a major risk factor for developing melanoma. Because many military personnel are stationed in sun-intense locales, however, sun exposure is often unavoidable. Furthermore, it is known that older military personnel develop melanoma at a higher rate than the age-matched controls in the general population. Unfortunately, the prognosis for patients with melanoma with distant metastases is usually poor. This grant proposal seeks to develop a new drug to improve the effectiveness of existing therapy for advanced melanoma and will therefore be widely beneficial to military personnel.