In 1991, the New England Journal of Medicine published results of a landmark study that transformed bone marrow transplantation. It showed that the antiviral drug ganciclovir could prevent cytomegalovirus, or CMV, disease — the leading infectious killer of transplant patients.
Dr. Joel Meyers of Fred Hutchinson Cancer Research Center, who founded the first program in the country to study and treat the unique infections that plague transplant patients, led the study. But the publication’s timing was bittersweet. The researcher whose finding would save so many lives had died of colon cancer weeks earlier. He was just 46.
Today, Fred Hutch infectious disease researchers are following in the footsteps of Meyers and his fellow and first author Dr. James Goodrich by helping to speed the approval of new, less toxic CMV drugs. The link is direct and concrete: Drs. Michael Boeckh and Elizabeth Duke are teasing new information from blood samples frozen and stored from Meyers’ 1989–1991 clinical trial.
“This is Joel’s legacy,” Duke said. “And it is the legacy that people who had bone marrow transplants back in 1989 are contributing to the state of the art in research and medicine for the current transplant recipients.”
Under the direction of Boeckh, who heads the Infectious Disease Sciences Program and designed the present study, Duke set out to show that viral load — the amount of CMV in a milliliter of blood — can serve as a surrogate endpoint in a clinical trial.
Finding a surrogate endpoint matters because drugs typically receive U.S. Food and Drug Administration approval based on clinical outcomes — in this case, CMV-related pneumonia or death. But what had been common in Meyers’ day is now, thanks to ganciclovir, rare. This otherwise good news complicates winning approval for new drugs that may have less toxic side effects.
A physician and mathematical modeler, Duke is tapping Meyers’ samples to show how viral load and its mathematical features (called kinetics) correlate with progression of CMV infection to CMV disease. The research is so promising that it was named best abstract of the year at February’s combined annual meetings of the American Society for Blood and Marrow Transplantation and the Center for International Blood & Marrow Transplant Research.
And late last year, the FDA approved letermovir, the first new drug for CMV in 15 years. Letermovir was approved using a novel CMV trial design, with preventing “clinically significant” CMV infection as the endpoint rather than CMV disease itself. Essentially, that translates to the viral load at which clinicians would preemptively treat patients to prevent disease.
“The drug is remarkable — highly effective, nontoxic,” said Boeckh, an author of the paper on the letermovir clinical trial, which was published in December in the New England Journal of Medicine. The work being done at the Hutch on the significance of CMV viral load, he said, was a critical part of the evidence that the FDA considered before it accepted that surrogate endpoint.
“I think Joel is smiling from heaven about that,” Boeckh said.
That Meyers would leave a lasting legacy despite his too-short life was not in doubt. Recruited to Fred Hutch by transplant pioneer Dr. E. Donnall Thomas, he published key studies that helped define the new field of infections in people with weakened immune systems even as Thomas was forging the field of bone marrow transplantation. Boeckh came to the Hutch in 1990 — the year Thomas won the Nobel Prize in physiology or medicine for his BMT work — to train under Meyers, whose devotion to training young scientists was such that, after his death, his widow and colleagues memorialized him in the Joel Meyers Endowment Scholarship, which has helped launch dozens of careers. Today Fred Hutch has one of the largest groups of infectious disease researchers of any cancer research center.
A lesser-known legacy, at least outside of scientific circles, is the collection of specimens from his and others’ research that the Hutch has saved over the decades.
“He had the vision to put these into the freezer,” said Boeckh, who along with Fred Hutch’s Dr. Larry Corey later fought to preserve the collection. “After Joel died, Larry was always fighting not to destroy these samples. ‘That’s blind hope,’ people would say. But now others are imitating us because they know the value.”
The Infectious Disease Sciences repository now contains more than 250,000 biospecimens left over from research projects, clinical trials and medical procedures. These specimens otherwise would have been discarded but have been kept, with the patients’ consent, to use in research. (Patients can and do still contribute their leftover specimens.)
Repository manager Terry Stevens-Ayers has worked with Boeckh for 26 years in the Hutch’s so-called “freezer-farm” trenches, starting from the days of “a lot of old Kenmores, like the kind you would have in your garage,” she said. If a freezer crashed in the middle of the night, Stevens-Ayers was the one who, alerted by an alarm, would race to campus to transfer invaluable samples to a standby freezer.
Today the repository, which continues to grow by about 16,000 samples per year, is housed in 27 freezers, including 18 biomedical freezers kept at minus 20 degrees Celcius, eight ultralow freezers at minus 70 C and one liquid nitrogen cryofreezer kept at minus 196 C.
The collection’s extraordinary time span allows scientists to study pathogens that cause infection at lower frequencies and also to study viral and bacterial evolution over time, Stevens-Ayers said.
“We can go back in time and apply new, more sensitive methods for pathogen detection to solve clinical mysteries,” she said. “And as new disease agents are discovered, the repository offers a ready-made source of samples for investigation of historical incidence and importance.”
Research using repository resources have led to improved infection monitoring and treatment in cancer patients. Although mostly used by infectious disease researchers, the collection is accessible to all Fred Hutch scientists and their collaborators for studies that are approved by the Hutch Institutional Review Board. Researchers from each of the center’s five scientific divisions have used the repository, resulting in more than 30 scientific publications to date with additional projects underway.
As Stevens-Ayers put it, “It’s a pretty big return for your buck in terms of research investment.”
Because of the biorepository, Duke has been able to go back and look for plasma samples for all the participants who were in Meyers’ trial. The company that originally made ganciclovir and that had sponsored the trial was later sold, and then its building burned down. So the only records of the trial are Meyers’ clinical charts — which the Hutch also saved along with those of all transplant patients — and the frozen samples.
“Basically, we are the only place in the world where a study like this could be done,” Duke said. “In part it’s because we were the first ones to be doing transplants — other places wouldn’t have had any samples to save. Joel’s and Larry’s and Michael’s legacy was realizing they were going to be important.”
Back in the day, Meyers detected CMV by spreading specimens on a plate of human cells. Unlike using a bacterial culture, where scientists can actually see bacterial cells growing, viruses reproduce by hijacking human cells, generally causing the host cell to die. To determine whether a virus is present in a specimen, scientists check to see how many human cells die in the plate — a process that takes days and does not particularly quantify how much virus is present.
Duke’s team, by contrast, was able to run PCR, or polymerase chain reaction, a faster and more sensitive technique that detects the virus’ DNA in the sample, directly measuring CMV load rather than cell death. It also allows researchers to see how many copies of the virus are present in a milliliter of plasma. (Funding for the PCR testing was provided by Merck & Co.)
“What’s great about Joel’s data set — and why it’s the only way we can do this study — is that in his trial, there is a placebo group, so we can see what the natural history of the viral load is coming up to the CMV-disease event,” Duke said. “Today, trial participants are not able to be randomized to placebo because that would be unethical given how much of a difference ganciclovir makes.”
PCR today allows physicians to give ganciclovir preemptively once a patient’s CMV load reaches a certain threshold. (It is too toxic to be given prophylactically to all patients from the start.) But that threshold varies from cancer center to cancer center.
By applying PCR to samples collected from Meyers’ placebo-controlled trial, Duke and Boeckh may be able to set standards for clinical practice. Knowing these thresholds also could be useful to treat and prevent CMV in patients undergoing new immunotherapy treatments as experimental CMV-specific T-cell therapies and vaccines become available.
Even with the approval of letermovir — which is nontoxic enough to be given prophylactically — infectious disease researchers would like to see additional new drugs or immunotherapies approved. One reason is to have alternatives if resistance develops.
In her winning abstract, Duke and her team showed that viral load is a predictor of CMV disease and CMV-related death. Duke plans to complete the project and publish the results using mathematical modeling skills honed under her primary research mentor, Dr. Josh Schiffer. And if she needs additional data, there are samples from a second Meyers trial in the freezer.
Working with Meyers’ samples has been professionally rewarding. But Duke has also felt a personal connection to a scientist she never met but whose work is legendary.
“Joel came here as a young infectious disease doctor trying to make a career as a researcher and trying to help prevent infections and infection-related deaths in transplant patients,” she said. “In that sense, I feel, well, that’s what I’m doing. Joel was known for his mentorship. I’ve been mentored by Michael, who was mentored by Joel, and that feels like a direct connection as well.”
Then there was the time she spent reviewing Meyers’ charts, deciphering handwriting, reading about his patients. She assumed, given that the trial was conducted 29 years ago, before so many advances in transplantation, that most of the patients were now dead.
She was wrong.
“As I was going through the charts, I realized that quite a few of these patients are still alive — about 30 percent of them — which really surprised me,” she said. “There are still more patients from the ganciclovir group alive than in the placebo group. It made me feel really good about what Joel did — and what the Hutch does.”
Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.