Paul M. Sondel, MD, PhD, CLIP Investigator

The research focus of Dr. Sondel’s proposal seeks to develop more effective therapeutic strategies for patients with melanoma. Each year, about 100,000 people in the USA get diagnosed with melanoma, and of those about 7,000 will die from the disease. Melanoma patients are grouped into different risk groups, and patients that get put into a risk group of advanced melanoma disease have a poor prognosis; after 5 years only about 20% of these patients will be alive. The goal of Dr. Sondel’s project is to design therapies, based on a more potent immune attack, geared towards improving the outcomes for these patients with melanoma by eliminating all of their melanoma and preventing it from ever coming back. 

A main strategy for Dr. Sondel’s project is to use drugs that can reverse the effects of certain epigenetic modifiers (or inhibitors of epigenetic modifiers), to directly slow the growth of melanoma cells, and more importantly, restore MHC expression to enable the immune cells to recognize and destroy the melanoma. He will use inhibitors of epigenetic modifiers to enhance the effects of immunotherapy, allowing for T cells that enter the tumor during immunotherapy treatment to recognize that MHC marker. Like many cancers, as T cells start to invade melanoma tumors, the melanomas may respond by increasing the expression of other markers called immune checkpoint inhibitors, like “PD-L1” or “CTLA4,” that can work to turn off the immune invasion. To avoid this, Dr. Sondel will also include treatment drugs that inhibit these immune checkpoints, called “immune checkpoint inhibitors” or “ICIs”, that will block the interactions of PD-L1 and/or CTLA4 with the T cells, allowing for the T cells to persist and maintain active anti-tumor function within the tumor until the tumor is destroyed. 

Putting these concepts together, Dr. Sondel plans to develop an approach that uses a combination of the standard therapy for melanoma with added immunotherapy together with inhibitors of epigenetic modifiers and ICIs. This treatment strategy is designed to unlock certain epigenetic modifications that have been turned on during the course of melanoma development, so that tumors are more recognizable by the immune system during the course of treatment. By including ICIs in the treatment, they can overcome treatment resistance, and together these agents should turn on the right immune cells to prevent the disease from recurring. This approach is designed to enable immune cells to enter the tumor, recognize it, maintain their anti-tumor activity, and prevent any tumor cells from ever returning. Importantly, both the epigenetic modifier inhibitors proposed in this research and ICIs are clinically available, so the regimen Dr. Sondel is developing in tumor-bearing mice could swiftly move into clinical testing, depending upon the results they are able to generate in these melanoma-bearing mice. Dr. Sondel’s goal is to provide more effective cures, and long healthy lives, for patients with melanoma.

Projects and Grants

Modulation of MHC expression via epigenetic regulation to enhance T cell response to immunotherapy in melanoma

University of Wisconsin-Madison | Melanoma | 2022