Jedd Wolchok, MD, PhD, FASCO

Improving response to immunotherapy in breast cancer patients.

Impact

Immunotherapy is a treatment strategy that utilizes the body’s immune defenses to fight off disease. Immune checkpoint blockade (ICB) is an innovative cancer treatment that uses a class of drugs known as immune checkpoint inhibitors that are designed to help the immune system recognize and destroy cancerous cells. This treatment strategy has been effective in patients with melanoma, lung, and other cancers, but has not been very effective for most breast cancers. The BCRF-supported research of Drs. Wolchok and Merghoub focuses on both developing new immune-based strategies and improving response to existing immunotherapies in breast cancer.

Progress Thus Far

Previously, Drs. Wolchok and Merghoub found that combining ICB with radiation therapy improved anti-tumor responses. The team has now shown that combining ICB with the chemotherapy cyclophosphamide also enhances anti-tumor responses in several preclinical models. To continue this work, they developed a liquid-biopsy assay to study changes in T cells—a type of immune cell that plays a central role in the anti-tumor immune response—in small amounts of blood. This novel technology enables the team to monitor T cells during treatments, assess the efficacy of combinatorial treatments, and determine optimal intervention times. The team has also developed a system to monitor immune and tumor cells simultaneously to understand what happens during tumor growth and in response to ICB. The team is now validating these tools in preclinical models of triple-negative breast cancer (TNBC). They plan to explore the effects of drugs that alter the pathways on immune cells, alone or combined with ICB. Furthermore, the team developed a platform to identify T cells that effectively recognize and kill tumor cells. They integrated this platform with single cell studies to pinpoint combination therapies that favor the generation of tumor-fighting T cells. Their research will inform the design of combination treatments that can overcome resistance to current immunotherapies in breast cancer to achieve long-term remission.

What’s next

Drs. Wolchok and Merghoub will continue optimizing therapeutic strategies to overcome immunotherapy resistance in breast cancer. In addition, Drs. Wolchok and Merghoub recently showed that inhibiting glycolysis, the primary energy pathway used by tumors, is an effective strategy in boosting anti-tumor immune responses in breast cancer. They plan to test whether a glycolysis inhibitor enhances the efficacy of immunotherapies in TNBC and determine the best regimen to maximize responses, guiding future clinical trials for breast cancer.