WSU labs discover 'armed killer' to attack infection in stem cell transplants
Using a modified product from a normal human donor, a team of investigators from the Wayne State University School of Medicine have discovered a new approach for controlling one of the most common and potentially life-threatening infections in stem cell transplant recipients.
Mayur Ramesh, M.D., tested human cell lines infected with human cytomegalovirus with a scientifically-altered donor product called T lymphocytes. The product was armed with a bispecific antibody, or artificial protein, that successfully targeted and killed the HCMV-infected targets.
HCMV is a common virus in the herpes family, spread by body fluids such as saliva. It typically goes unnoticed in healthy people, according to the U.S. Centers for Disease Control and Prevention, but is dangerous to those with compromised immune systems, including organ transplant recipients. Among every 100 adults in the United States, 50 percent to 80 percent are infected with CMV by age 40, the CDC states.
The two-year multidisciplinary project at WSU is based on technology developed in the lab of Lawrence Lum, M.D., professor of Oncology, Medicine, Immunology and Microbiology in Wayne State's School of Medicine, and scientific director of the Bone Marrow Transplantation and Immunotherapy Program at the Barbara Ann Karmanos Cancer Institute in Detroit.
The project itself was initiated by Ramesh during a Transplant Infectious Diseases fellowship at Karmanos. Ramesh was mentored by both Lum and Philip Pellett, Ph.D., a WSU professor of Immunology and Microbiology.
While a number of methods have been developed to control HCMV infections in stem cell transplant recipients, this approach is a notably unique option for an important and difficult problem, Pellett said.
"Dr. Ramesh did nearly all of the experiments. I mentored on the individual cytotoxicity experiments, and Dr. Pellett provided mentorship for the virological aspects of the experiment," Lum said. "This is an outstanding example of how a clinical infectious disease fellow can work in two labs with two mentors and come up with a unique product."
"Cooperation from personnel from both laboratories was thus instrumental in making the project work," Pellett added.
Ramesh is now a senior staff physician with the Henry Ford Health System and continues to collaborate on the project. Other contributors to the project include current Infectious Diseases fellow Nuttanun Suramaethakul, M.D., and former Infectious Diseases fellow Subhashis Mitra, M.D.
Pellett said the outcome of the project could reach patient bedsides within five years.
"Dr. Lum has already taken related approaches for tumor killing into clinical trials," he said. "We are working to complete the preclinical studies needed to fully justify a clinical trial, and have started to apply for financial support for the next iterations of this project. If we can garner the necessary support, it is possible for this approach to be tested in humans within five years."
The two years of work thus far, performed between 2009 and 2011, were funded by the National Cancer Institute of the National Institutes of Health – project numbers R01 CA092344 and R01 CA140314, WSU’s Division of Infectious Diseases and start-up funds from KCI and WSU. A U.S. patent application titled "Polyclonal bispecific antibody compositions and method of use," has been filed.
A paper, "Targeting Cytomegalovirus-Infected Cells Using T Cells Armed with Anti-CD3 x Anti-CMV Bispecific Antibody," is
slated for publication in the July 2012 issue of the Biology of Bone Marrow Transplantation, the journal of the American Society for Blood and Marrow Transplantation, but is available online at www.pubmed.gov