Abramson Cancer Center Support Grant

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 21-100. This application to the Early-stage Surgeon Scientist Program (ESSP) sets forth a three-year research proposal and career development plan to further the career of Dr. Jennifer Zhang as a surgeon-scientist focused on studying breast cancer immunobiology. Dr. Zhang’s primary clinical and research interest is hormone receptor positive (HR+) luminal breast cancer. This subtype of breast cancer is generally poorly responsive to chemotherapy, with low rates of pathologic complete response after neoadjuvant chemotherapy. Patients with locally advanced disease have poor long-term prognosis. New therapies are needed to improve pCR and survival. Although the use of immune checkpoint blockade (ICB) in combination with chemotherapy has recently been approved for use in metastatic and high-risk in triple negative breast cancer (TNBC), efficacy has not been demonstrated in HR+ breast cancer. This may be due to the immunologically cold environment of HR+ luminal breast cancers, where immune infiltration, including lymphocytes, is sparse. Using an orthotopic mouse model of HR+ luminal breast cancer, Dr. Zhang has demonstrated the ability of agonistic CD40 antibody to activate dendritic cells (DCs) and improve T cell function, with a significant anti-tumor effect that is dependent on CD8 T cells. Dr. Zhang hypothesizes that in cold, poorly immunogenic HR+ luminal breast cancers, a dysfunctional DC phenotype contributes to poor anti-tumor immunity, which may be reversed through DC activation via CD40 agonism to allow synergy with checkpoint blockade and chemotherapy. This proposal aims to explore this hypothesis via the following specific aims: (Aim 1) Determine the mechanism of agonistic CD40 therapy in murine HR+ luminal breast cancer, and (Aim 2) Define the landscape of CD40 expression in human HR+ luminal breast cancer. In support of her proposal, Dr. Zhang will have an invested and talented team of physician scientists, including her primary mentor Dr. Robert Vonderheide, as part of her advisory committee. This committee will provide guidance for her scientific research, training, and career development. In addition to being part of a well- funded and established laboratory environment, Dr. Zhang will also benefit from the strong research infrastructure at the University of Pennsylvania, including excellent core facilities and a culture of collaboration across the university and health system. Dr. Zhang’s compelling research proposal and tailored career development plan will provide a stepping stone towards her goal of becoming an independent surgeon scientist with an impactful line of investigation in breast cancer immunobiology.