Dr. Rainer Storb receives $12.9M to study blood stem-cell therapies for immune deficiencies; Dr. Julie Overbaugh studies HIV 'superinfection' to provide clues for better vaccine design
Dr. Rainer Storb, head of the Transplantation Biology Program at Fred Hutchinson Cancer Research Center, has received a $12.9 million grant from the National Heart, Lung, and Blood Institute to improve treatments for patients with inborn diseases of the immune system and red blood cells.
Storb and collaborators will launch a five-year, bench-to-bedside research program that seeks to refine treatments based on blood stem-cell transplantation for immune deficiencies, such as the condition commonly known as “bubble-boy disease,” and noncancerous disorders of red blood cells, such as sickle-cell disease. Their goal is to make transplantation safer and more widely available to people facing these diseases.
“Current approaches at cell and gene therapy for lethal noncancerous diseases of the blood and immune systems have inherent toxicities that may affect patients for the rest of their lives,” Storb said. “The targeted therapies proposed under this grant aim to eliminate these toxicities.”
Storb will lead the clinical-research portion of the program together with Hutch colleagues Drs. Ann Woolfrey and Lauri Burroughs, testing less-toxic approaches that could prevent dangerous side effects in patients receiving transplants of blood stem cells for their diseases. The program’s preclinical research, which will eventually feed into the clinic, will be led by Fred Hutch colleagues Drs. Brenda Sandmaier and Hans-Peter Kiem, with support from resource cores led by Drs. Oliver Press, a clinical researcher at the Hutch, and Dr. David Rawlings, an immunologist at Seattle Children's and the University of Washington.
The research will test numerous cutting-edge methods. For example, one set of experiments will test the use of targeted immune system molecules, called monoclonal antibodies, to shut down harmful immune responses that could cause the patient’s body to reject partially matched transplants. (Partially matched transplants are often the only option for patients of racial or ethnic minority backgrounds who cannot find a fully matched donor, but they come with a risk that they will be rejected or even begin to attack the patient’s body.) In another set of studies, a genetic “safety switch” is inserted into donor immune cells prior to transplant, ensuring they can be turned off if they start to go haywire.
This program builds on almost 35 years of large-scale research funding from NHLBI that Storb received to develop and improve transplantation of blood stem cells for noncancerous blood diseases.
"Superinfected" HIV-positive individuals — those who’ve been infected by independent strains of HIV from different partners — produce neutralizing antibodies to HIV that appear to target a wide range of the virus’ external structures, according to a new study published today in PLOS Pathogens by Dr. Julie Overbaugh of Fred Hutch's Human Biology Division. The work, which demonstrates that superinfection may produce a broader, and possibly more effective, antibody response than infection with a single HIV strain, could help inform optimal vaccine design.
Neutralizing antibodies protect cells from HIV infection, but developing a vaccine that can elicit them has been an uphill battle. Even in naturally infected people, neutralizing antibodies may take years or even decades to form, which isn’t feasible for a vaccine, Overbaugh said. In a study also led by Valerie Cortez, the first author of today's paper and a student in the joint Fred Hutch / University of Washington Molecular and Cellular Biology Program, Overbaugh's group had already shown that superinfected individuals often produce an especially strong neutralizing antibody response, which, in some cases, arises more quickly than seen in singly infected patients.
“The idea is that exposing people to a broader mix of antigens and genetic diversity would produce a better response,” Overbaugh explained. Superinfected HIV-positive people provide a “natural case” in which to test this hypothesis. Drawing from a study of high-risk women initiated more than 20 years ago, Overbaugh’s team has amassed what is currently the largest group of superinfected people: 21 individuals from whom they have collected blood samples beginning prior to the initial infection.
When infection with a single type of HIV produces broad neutralizing antibodies, these antibodies generally focus on the same four structures on the virus. However, it was unknown whether neutralizing antibodies from HIV-superinfected people form the same response pattern. Cortez and Overbaugh and their colleagues found that the neutralizing antibodies from superinfected patients do not focus specifically on these four areas of the virus.
“We think the response is probably polyclonal,” or made up of antibodies that bind to a wide range of viral structures, Overbaugh said. The findings suggest that developing an HIV vaccine with a variety of potential antibody targets may produce a more protective antibody response. “It might be a better way. Much like using a combination of drugs, it could make it harder for the virus to escape.”
The best strategy remains to be determined, Overbaugh said. It could be as simple as adding more HIV structures to a single vaccine dose, or giving sequential doses, each with a different spectrum of potential antibody targets, she noted. Now, her group is focusing on cloning the antibodies from superinfected individuals to discover if the response truly is polyclonal and to which targets, exactly, these antibodies bind.