A $328,000 National Cancer Institute (NCI) grant will enable researchers at Dartmouth's and Dartmouth-Hitchcock's Norris Cotton Cancer Center (NCCC) to investigate one of the mechanisms that may be responsible for the body's inability to fight COVID-19.
COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Antibodies produced by a patient can potentially exacerbate a viral disease, such as COVID-19 through a process called "antibody-dependent enhancement" (ADE). The NCI grant will fund research co-led by the NCCC laboratory of Paul Guyre, PhD, who has a 35-year history of studying antibodies and the receptors on human cells to which they bind, and by Steven Fiering, PhD, Professor of Microbiology and Immunology at the Geisel School of Medicine at Dartmouth and member of the Immunology and Cancer Immunotherapy Research Program at NCCC.
Guyre and Fiering's team will investigate the possibility that some patients make antibodies that do not protect against SARS-CoV-2 virus, but rather enhance the ability of the virus to infect cells. "ADE has been shown to occur previously with Dengue, Zika, the first SARS-CoV, and other coronaviruses," notes Guyre. "Such nonprotective antibodies could be one reason why some people do much worse than others with this virus, which can vary from zero symptoms in some infected people to death in others."
The team's goal is to rigorously analyze antibodies that are generated by vaccines as well as antibodies that are present in recovered patients' blood. "With this assay we would investigate the correlation of patient outcome with the presence of 'good' or 'bad' antibodies," explains Guyre. "We will test the hypothesis that poor outcomes are associated with higher levels of 'bad' antibodies and determine whether a specific vaccine is making more of one or the other type of antibody."
It is important to study potential antibody enhancement of SARS-CoV-2 virus infection, since it has been a problem in epidemics caused by other viruses such as Influenza, Zika and Dengue. If successful, the Guyre and Fiering team's analyses will determine conditions under which enhancement can happen, identify patients in which it is occurring, and potentially save lives of COVID-19 patients. This same assay approach would then be available for application in future viral epidemics that may also involve ADE. "Our research would first provide a clearer understanding of one potential cause of the striking range of symptoms caused by this virus. This information and the assay for ADE we are developing will likely help clinicians understand who is most likely to do poorly, and enable different treatment approaches that would save lives," says Guyre.
The NCI grant will be awarded to Principal Investigator and NCCC Director, Steven D. Leach, MD. "Our goals are to develop a model capable of screening therapeutic antibodies and to rigorously examine negative effects of SARS-CoV2 antibodies on immune cells. Since 1983, our team has published more than 40 definitive papers on immune biology and developed novel models to explain the mechanisms of action of therapeutic antibodies, some of which we created," says Leach. "Now, in these unprecedented times, our scientists are having to repurpose their valuable skills and expertise in cancer immunology, pathology, and drug and vaccine development and apply them toward innovating new ways to diagnose and treat COVID-19. It has been immensely inspiring to see how our combined Dartmouth College, Geisel School of Medicine, and Dartmouth-Hitchcock Health research communities have partnered in action to help the nation through this crisis."
The project, entitled "SARS-CoV-2 Antibodies: Protective or Pathogenic?" will be co-led by the Paul Guyre laboratory and by Steven Fiering, PhD. Research team members include Lab Manager Jane Collins, Senior Researcher Jonell Hamilton, Principal Scientific Consultant Cheryl Guyre, along with NCCC's Immunology and Cancer Immunotherapy Research Program members Margaret Ackerman and Edward Usherwood, and with Director Jacqueline Smith and her team at the Immune Monitoring Laboratory (DartLab) at the Geisel School of Medicine at Dartmouth.
Paul Guyre, PhD, is an active Emeritus Professor of Microbiology and Immunology at the Geisel School of Medicine at Dartmouth and Member of the Immunology and Cancer Immunotherapy Research Program at Dartmouth's and Dartmouth-Hitchcock's Norris Cotton Cancer Center. His research in immunobiology focuses on antibody-based immunotherapy and white blood cell function. Guyre is the co-founder of Medarex, the company that developed FDA-approved human antibodies including the game-changing cancer immunotherapeutic checkpoint antibodies ipilimumab and nivolumab.
Steven N. Fiering, PhD, is a Professor of Microbiology and Immunology at the Geisel School of Medicine at Dartmouth, and a member of the Immunology and Cancer Immunotherapy Research Program at Dartmouth's and Dartmouth-Hitchcock's Norris Cotton Cancer Center. Research interests include development of in situ vaccinations to stimulate immune response and generate therapeutic anti-tumor immunity.
About Norris Cotton Cancer Center
Norris Cotton Cancer Center, located on the campus of Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH, combines advanced cancer research at Dartmouth College's Geisel School of Medicine in Hanover, NH with the highest level of high-quality, innovative, personalized, and compassionate patient-centered cancer care at DHMC, as well as at regional, multi-disciplinary locations and partner hospitals throughout NH and VT,. NCCC is one of only 51 centers nationwide to earn the National Cancer Institute's prestigious "Comprehensive Cancer Center" designation, the result of an outstanding collaboration between DHMC, New Hampshire's only academic medical center, and Dartmouth College. Now entering its fifth decade, NCCC remains committed to excellence, outreach and education, and strives to prevent and cure cancer, enhance survivorship and to promote cancer health equity through its pioneering interdisciplinary research. Each year the NCCC schedules 61,000 appointments seeing nearly 4,000 newly diagnosed patients, and currently offers its patients more than 100 active clinical trials.