Samuel H. Cheshier, MD

As a pediatric neurosurgeon, I witness first-hand the devastation that malignant brain tumors cause both the patients and families. The desire to help these people motivates me to conduct basic science research, with the goal of translating experiments into therapies. My laboratory has been utilizing a powerful immune-therapy strategy where CD47-SIRPa interactions between tumor cells and macrophages are blocked by Hu5F9-G4 in combination with potent immunotherapies including anti-cancer targeted monoclonal antibodies (anti-PDL1, anti-CD44, anti-Her2/Neu, anti-GD2), and modulators of macrophage activity (anti-CD40). My clinical practice specializing in brain tumor surgery has provided my laboratory with a large number of patient-derived malignant brain tumors from both pediatric and adult patients, which have already been used to conduct an excellent preclinical evaluation of Hu5F9-G4 against five pediatric malignant primary CNS tumors. While I was faculty at Stanford, I was in charge of the preclinical development of Hu5F9-G4 against malignant brain tumors, and I was a participant in the anti-CD47 Disease Team that helped develop the therapy into Phase 1 clinical trial. Since accepting my position at the Huntsman Cancer Institute, University of Utah School of Medicine as Director of Pediatric Surgical Neuro-Oncology, one of my laboratory’s main goals is to enhance anti-CD47 mediated phagocytosis by promoting the expression of pro-phagocytosis signals on brain cancer cells by irradiation. Irradiation is a well-known enhancer of pro-phagocytosis signal presentation on tumor cells. For example, calreticulin and phosphatidylserine are key pro-phagocytosis signals and are elevated in response to irradiation. I have developed preliminary data demonstrating anti-CD47 in combination with irradiation increased macrophage phagocytosis of human glioblastoma in vitro and increased survival in human glioblastoma-mouse orthotopic PDX models. Given the known efficacy of irradiation against malignant brain tumors, and the large medical infrastructure already present to deliver irradiation to patients, I feel my proposed studies to combine irradiation with anti-CD47, will provide significant data to justify clinical trials utilizing this combination. My current and previous research history have provided me a deep understanding (mechanism, efficacy, toxicity, combinatorial strategies) of anti-CD47 therapy in general. My laboratory can conduct the entire range of preclinical experiments testing anti-CD47 in vitro, as well as, in mouse models (human-mouse PDX, mouse models of primary brain tumors) to obtain data to justify and help design human trials in brain tumor patients. I believe anti-CD47 will be a foundational immune therapy that will be used as a key reagent in combination with other immune therapies and standard of care treatments."