Craig M. Brackett

Biography:

Dr. Brackett joined the faculty in the Department of Cell Stress Biology at Roswell Park Comprehensive Cancer Center in October 2021. He earned his PhD in Tumor Immunology from the Roswell Park Graduate Division of  the State University of New York at Buffalo under the mentorship of Dr. Sandra Gollnick.His work defined a pivotal role for a highly integrated IL-17-CXCL2 axis in regulating neutrophil homing to tumor draining lymph nodes (TDLNs) post-induction of sterile inflammation by photodynamic therapy (PDT). These findings challenged conventional wisdom that neutrophils are incapable of both migrating to TDLNs and stimulating adaptive immunity and provided the groundwork for further investigating an underappreciated role for neutrophils in the generation of anti-tumor immunity following induction of acute inflammation.

Dr. Brackett’s post-doctoral training with Dr. Andrei Gudkov led to seminal publications showing that their toll-like receptor (TLR) 5 agonist, entolimod, exhibits immunotherapeutic activity in multiple pre-clinical metastatic tumor models. Entolimod is an engineered and pharmacologically optimized Salmonella flagellin derivative and, importantly, has successfully completed Phase I safety trials in nearly 200 subjects. Systemic administration of entolimod triggers acute inflammation characterized by activation of immunoregulatory signaling pathways in hepatocytes, rapid accumulation of neutrophils and NK cells to the liver, and development of durable CD8+ T cell dependent anti-tumor immunity. These findings are informing the rationale design of novel and efficacious TLR5 agonist based immunotherapies to boost anti-tumor immunity against metastatic disease.

In addition to its immunotherapeutic activity, entolimod is among the most powerful experimental radiation countermeasures and shows efficacy in rodents and non-human primates as a prophylactic (radioprotection) and treatment (radiomitigation) modality for normal tissues but importantly not tumors. Dr. Brackett recently uncovered that in contrast to radioprotection, neutrophils are essential for the radiomitigative activity of entolimod against lethal acute radiation syndrome (ARS), a major cause of lethality following radiation disasters that manifests as death of hematopoiesis in the bone marrow (BM). Mechanistically, neutrophils express functional TLR5 and following entolimod stimulation release MMP-9, which is accompanied by the recovery of hematopoiesis in the BM and rescue from death caused by ARS. Unveiling this novel TLR5-neutrophil-MMP-9 axis of radiomitigation has opened new opportunities for developing efficacious countermeasures to treat pathologies associated with ARS following scenarios of accidental radiation disasters or myeloablative chemotherapy in the case of cancer patients.