Celebrated kidney transplant expert likes to joke that he publishes his research regularly in the prestigious scientific journal Nature — that is, once every 51 years.
The first paper, published in 1974, reported on , leading to organ failure.
The second, published just last month, , representing a career’s worth of clinical observation and scientific inquiry, with many successes, failures and a few serendipitous discoveries along the way.
The newest paper follows a , a newly developed drug that suppresses a process now known as antibody-mediated rejection (ABMR), which is the culprit behind about half of all transplanted kidney failures.
Researchers in Vienna, Berlin and Edmonton, led at the ¾ÅÐãÖ±²¥ by Halloran and his team, examined biopsies at the molecular level from 10 patients treated with the drug and 10 placebo patients at the pre-treatment, end-of-treatment (six months) and post-treatment stages (six months later).
All patients with active rejection who took the drug showed suppression of the rejection activity. The treated group also showed less damage to their kidney tissue than the placebo group, even after treatment was stopped, suggesting the drug could delay organ failure.
Though the drug must still undergo further clinical trials, Halloran hopes that one day it will be used on a regular basis to prevent kidney failure indefinitely in some patients.
“The goal is that when you do an organ transplant, it doesn’t fail,” he says. “We hope this new agent will be released for therapy and that people with this form of rejection can live normal lives, whereas previously, they’d have been locked into failure within a few years.”
“The real story comes from patients”
Back when Halloran’s career first began in London, England, organ transplantation was still a relatively new field and organ rejection was poorly understood. It was known to be an immune response, but it wasn’t clear how it worked. Halloran showed in mice that while some forms of graft rejection involve T cells, others might be caused by a different part of the immune system: the antibodies produced by B cells.
That first 1974 paper showed that natural killer cells (NK cells) in mice could recognize antibody bound to the antigens involved in transplant rejection, and this could be a potential mechanism of organ transplant rejection. But strangely mice did not seem to actually use this mechanism. Later, in Toronto and Edmonton, Halloran began to measure the expression of the genes in the tissues, and began to recognize the actual disease process in patients.
“We were the first to recognize that humans can get antibody-mediated rejection, and that it damages the tiny blood vessels — the microcirculation. We saw that just with the microscope and looking at biopsies from patients. So the idea started in mice, but the real story comes from patients.”
Halloran moved to the U of A and technological improvement allowed a leap forward: His team won a $12-million grant from to develop much more comprehensive, genome-wide analysis — the ability to measure the expression of 19,000 genes in each transplant.
Halloran established the ¾ÅÐãÖ±²¥ Transplant Applied Genomics Centre (ATAGC), and the Molecular Microscope Diagnostic System (MMDx) was born. The system is now licensed to and is used commercially in Canada, the United States, Europe and Brazil. First developed to look at kidney transplant biopsies, it is now used to assess other heart, lung and liver transplants and inflammatory bowel diseases at the molecular level.
The research team was able to demonstrate
“Probably 50 per cent of heart and kidney rejection is caused by antibody damage to the graft, and we saw that the genes in antibody problems are different from the genes in T cell problems,” he remembers.
It was a breakthrough because although the symptoms are the same — organ failure — the mechanisms behind those failures are not.
“It’s just like with pneumonia: Are you looking at pneumococcal pneumonia or are you looking at tuberculosis? They’re both pneumonias, but they’re very different,” Halloran says. “You have to specify which disease you’re looking at. Once we started honing in on a specific disease, then treatment options could emerge.”
Narrowing down treatment possibilities
Halloran and his ATAGC colleagues further narrowed in on a potential target for treatment in a 2010 paper published in the American Journal of Transplantation, . Natural killer (NK) cells are activated when antibodies identify a foreign target, and they were showing up regularly in ABMR biopsies examined using the MMDx system.
But there was a wrinkle along the way: The 1974 studies that generated the idea were in mice, but it turns out that while mice are excellent stand-ins for humans in many pre-clinical trials, their NK cells don’t behave like ours. So the full extent of antibody-mediated rejection was not apparent until the team developed the ability to study human transplant tissues.
“We didn’t know it at the time, but humans and mice separated in their NK cells about 60 million years ago, and we got a type of NK cell that can kill cells coated with antibody, and they didn’t,” explains Halloran. “Mouse NK cells can interact with antibody but they cannot kill the way human NK cells do.”
Collaborators in France, Germany, Austria, the Czech Republic, Poland and Australia worked together with the Edmonton team to identify a monoclonal antibody that could disrupt NK cells in humans.
“There were many things we tried that did not suppress this disease. It’s been a very, very tough disease to handle, and there were many failures,” Halloran says.
Then serendipity kicked in. Drugs that target a molecule called CD38 were designed to kill malignant plasma cells in myeloma patients but also reduced natural killer cells. The mechanism is still not fully understood, but it works. While felzartamab was first designed to kill plasma cells, its ability to suppress NK cells is why it is effective in treating antibody-mediated rejection in transplant patients.
“People were trying to kill myeloma cells by making monoclonals against plasma cells. Anti-CD38 antibodies have been a real breakthrough in myeloma,” Halloran explains. “By chance, their target on the plasma cell, CD38, is also expressed on NK cells, and so now we have an antibody that can control NK cells.”
In the Phase 3 clinical trials of felzartamab, the researchers have found that by suppressing NK cells, they can suppress rejection activity.
“We’re not exactly sure what it does with the NK cells. All we know is that the NK cells in the blood fall dramatically as soon as you give people the antibody. And antibody-mediated rejection activity in the kidney goes way down,” Halloran says.
“We now think we have a tool, at least one tool, that can help suppress this disease and extend the life of heart and kidney transplants,” Halloran says. “So that’s our story. It goes back a long way.”
“Make people better and change their lives”
Halloran foresees a time when kidney and heart transplant recipients who develop antibody-mediated rejection can live long, healthy lives by being treated regularly with antibodies like felzartamab, much like how chronic illnesses such as rheumatoid arthritis, Crohn’s and colitis are treated.
“We haven’t cured the disease, but we can suppress the activity and make people a lot better and change their lives,” he says.
¾ÅÐãÖ±²¥ patients will be able to participate in the next phase of felzartamab trials, Halloran hopes. And patients have already made a huge contribution by adding to an international repository of 20,000 biopsies that Halloran has collected.
“We’re very grateful to the patients who gave us a gift of their tissues,” Halloran says. “We keep the genetic material from biopsies so that in the future, other systems may be able to use technology in a different way. Each biopsy creates a massive data file, and we can do research with those data files forever.”
Halloran will continue to tell his story and pitch the findings at meetings of his colleagues around the world, including the coming up in August in San Francisco. He says the excitement is palpable every time he explains the breakthrough.
“We’ve had very little activity in organ transplantation research by pharma companies in the last 20 years,” he says. “We’re trying to change that and get the energy back in the field and get investment back.”
Halloran is a professor in the Department of Medicine and a member of the ¾ÅÐãÖ±²¥ Transplant Institute. His research was funded by Genome Canada, , Thermo Fisher Scientific, and .
