Research Interests:Defining novel approaches to dampen stress as a means to augment anti-tumor immunity of toll-like receptor 5 agonists; Identifying and developing effective countermeasures to treat pathologies associated with acute radiation syndrome.
About Craig M. Brackett
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.
- Assistant Professor of Oncology
- Department of Cell Stress Biology
Education and Training:
- 2012 - PhD - Tumor Immunology, State University of New York at Buffalo, Roswell Park Graduate Division, Buffalo, NY
- 2006 - BS - Biochemistry & Biology, St. John Fisher College, Rochester, NY
- Radiation Research Society
- The American Association of Immunologists
- 2011-2015 - Postdoctoral Fellow, Roswell Park Comprehensive Cancer Center, Department of Cell Stress Biology, Buffalo, NY
- 2006-2011 - Graduate Student, State University of New York at Buffalo Roswell Park Graduate Division, Buffalo, NY
Honors & Awards:
- 2016 - Ten Under 10 Award, St. John Fisher College, Rochester, NY
Dr. Brackett’s research is devoted to defining novel strategies to dampen stress response pathways as a means to augment anti-tumor immunity of TLR5 agonists. Cancer treatments (i.e., radiotherapy, chemotherapy, immunotherapy) and environmental cues (i.e., everyday life experiences especially those for cancer patients) often engage stress response pathways that cause normal tissue damage, diminish anti-tumor immunity, and thereby lead to suboptimal clinical responses. Our pivotal discoveries have shown that our TLR5 agonist entolimod not only reduces tissue-damaging stress response pathways but also stimulates durable anti-tumor immunity. Although these activities of entolimod were initially attributed to TLR5 stimulation on hepatocytes, Dr. Brackett recently uncovered that stimulation of TLR5 on neutrophils is essential for healing radiation-induced damage to normal tissues. These findings have underscored a potential dual role for neutrophils in dampening tissue-damaging stress and triggering anti-tumor immunity of TLR5 agonists. This new mechanistic knowledge is being translated into novel approaches to broaden the therapeutic window of current cancer treatments. These efforts also include developing novel and efficacious countermeasures to treat pathologies associated with ARS such as those that manifest following accidental exposure to radiation or myeloablative chemotherapy.
Brackett CM*, Greene KF, Aldrich AR, Trageser NH, Pal S, Molodtsov I, Kandar BM, Burdelya LG, Abrams SI, Gudkov AV. Signaling through TLR5 mitigates lethal radiation damage by neutrophil-dependent release of MMP-9. Cell Death Discov. 2021 Sep 28;7(1):266. doi: 10.1038/s41420-021-00642-6. PMID: 34584068. *corresponding author
Mett V, Kurnasov OV, Bespalov IA, Molodtsov I, Brackett CM, Burdelya LG, Purmal AA, Gleiberman AS, Toshkov IA, Burkhart CA, Kogan YN, Andrianova EL, Gudkov AV, Osterman AL. A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications. Commun Biol. 2021 Apr 12;4(1):466. doi: 10.1038/s42003-021-01978-6. PMID: 33846531; PMCID: PMC8041767.
Brackett CM, Kojouharov B, Veith J, Greene KF, Burdelya LG, Gollnick SO, Abrams SI, Gudkov AV. Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8+ T-cell axis. Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):E874-83. doi: 10.1073/pnas.1521359113. Epub 2016 Feb 1. PMID: 26831100; PMCID: PMC4763744.
Brackett CM, Muhitch JB, Evans SS, Gollnick SO. IL-17 promotes neutrophil entry into tumor-draining lymph nodes following induction of sterile inflammation. J Immunol. 2013 Oct 15;191(8):4348-57. doi: 10.4049/jimmunol.1103621. Epub 2013 Sep 11. PMID: 24026079; PubMed Central PMC3795982.
Burdelya LG, Brackett CM, Kojouharov B, Gitlin II, Leonova KI, Gleiberman AS, Aygun-Sunar S, Veith J, Johnson C, Haderski GJ, Stanhope-Baker P, Allamaneni S, Skitzki J, Zeng M, Martsen E, Medvedev A, Scheblyakov D, Artemicheva NM, Logunov DY, Gintsburg AL, Naroditsky BS, Makarov SS, Gudkov AV. Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist. Proc Natl Acad Sci U S A. 2013 May 14;110(20):E1857-66. doi: 10.1073/pnas.1222805110. Epub 2013 Apr 29. PMID: 23630282; PMCID: PMC3657788.