New research suggests that doctors may have had an incorrect understanding of how a standard treatment for an incurable blood cancer works to prolong lives. The therapy, based around high doses of chemotherapy or radiation, looks like it may actually be an immunotherapy — that is, a treatment that stimulates the patients’ own immune systems to help fight their cancers.
The scientists say that these “definitive” and “hitherto unexpected” findings in mice open the door to new strategies to harness and augment this effect and, hopefully, improve treatment outcomes for patients with multiple myeloma.
The therapy is called autologous transplant. It typically involves blasting a patient with a high dose of chemotherapy, and sometimes radiation, then giving back the patient’s own pre-collected blood-forming stem cells. The point of those cells is to re-establish normal blood and immune function after it had been destroyed, which would otherwise kill the patient. But it turns out the cells are doing something else perhaps even more important.
“Autologous transplant is more than just chemotherapy. It does create an environment for resetting the immune response against myeloma, and there’s a number of therapeutic maneuvers you can do to try and enhance that,” said Dr. Geoffrey Hill of Fred Hutchinson Cancer Research Center, the senior researcher on the studies.
The pair of new studies were published on Tuesday in the Journal of Clinical Investigation and in August in the journal Blood. The research was conducted at QIMR Berghofer Medical Research Institute in Brisbane, Australia, where Hill led the blood stem cell transplant and cancer programs before coming to Fred Hutch in July 2018.
The team anticipates opening clinical trials to test transplant in combination with certain immune-boosting drugs for treating myeloma.
“As a scientist, it's a wonderful thing to be involved in research that may directly impact patients' lives,” said Simone Minnie of QIMR Berghofer, who carried out these experiments under Hill’s guidance as part of her Ph.D. studies. “I will be excited to see these immunotherapies go into the clinic in combination with auto-transplant.”
Autologous transplant has been a standard of care for multiple myeloma, and certain other conditions, for decades. Patients can live for years in good health after autologous transplant plunges their myeloma into dormancy, especially when the therapy is coupled with other recent improvements in myeloma care. But the cancer almost always comes back, and most people who have been diagnosed with myeloma will eventually die of it.
The story of how autologous transplant helps patients live longer has always been that it’s all about the chemo or radiation killing off the myeloma cells.
But scientists have been learning more and more about how powerful the immune system can be in controlling cancer. New immunotherapies are emerging all the time for treating more types of cancer based on these lessons.
Researchers have known that the immune system can recognize myeloma cells, and there have been hints from human studies that the immune response may be helping control some patients’ myeloma.
So Hill and colleagues decided to re-examine the old story.
“In an age of immune therapies, we decided to look at that and challenge that a little more,” said Hill, director of Hematopoietic Stem Cell Transplantation at Fred Hutch and the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research.
The time was also right for another reason. They finally had a way to study the question in depth: After years of work, the team had developed a system in mice with human-like myeloma that could undergo transplantation procedures in the lab.
What the scientists found surprised them. No matter how they looked at the problem, they saw that long-term control of the mice’s cancer came from immune cells called T cells, transplanted back into their bodies after radiation, recognizing and killing the myeloma cells. And when the cancers returned, it was because the T cells were too tired to mount an attack any longer.
The immune cells the mice received after transplant were no different from those they’d had in their bodies before the transplant. So why could they attack the cancer so well after radiation but not before?
Even though the immune system can often recognize cancer, cancer is an expert in the dark art of shutting down its attacks. So, while the mice’s immune systems had known the cancer was there, it was just not able to do much about it. That all shifted with the high dose of radiation that kicked off the transplant procedure.
Both radiation as well as chemotherapy (which is most often used in human autologous transplant) cause inflammation — a state of immune high-alert. They also deplete the body’s supply of normal immune cells. That creates a demand for replacements, which stimulates the newly transplanted stem cells to multiply.
In this environment, Hill explained, the T cells “don’t behave normally. They expand and proliferate much more dramatically than they would normally, and so you’re revving the whole immune response up.” The picture that emerges from Hill’s team’s studies is that in their state of heightened excitement, any myeloma-specific T cells in the bunch multiply even more aggressively because they recognize traces of their old foe.
The other form of blood stem cell transplantation — called “allogeneic,” meaning that the cells come from another person — has long been recognized as a form of immunotherapy. Because the patient’s new immune cells come from a different person, they readily recognize the patient’s cells as foreign and attack them. The observation of this potentially powerful effect, made in the late 1970s by the Hutch scientists who pioneered allogeneic transplant, laid the groundwork for T-cell–based immunotherapies that are being developed today.
The researchers identified a defined set of signals sent by the transplanted immune cells that either help or hinder the T cells as they go on their rampage against myeloma. When they gave the mice drugs right after transplant to manipulate these signals, it amplified the anti-cancer power of the newly infused T cells — and, most importantly, dramatically extended the mice’s survival.
For example, close to 80 percent of mice survived for four months after transplant if they received a drug that stimulates the important T-cell helping signal the scientists identified. In comparison, only about 25 percent of mice that underwent the transplant procedure without the drug lived that long. The researchers found that adding a second type of immune-modulating drug enhanced the T cells’ anti-myeloma response even more in the weeks post-transplant.
Hill and his colleagues are now in negotiations with drugmakers to open clinical trials next year that would test some of the drugs that seemed so promising in mice. The idea would be to give one or more of these drugs to multiple myeloma patients shortly after transplant to boost the anticancer immune response.
Previous clinical trials of immune-boosting drugs in myeloma haven’t been particularly successful. Based on his team’s research, Hill suspects that it is because by the time the patients got them, their T cells were already irreversibly worn out.
“We've found that timing is everything,” Minnie said. According to their mouse data, “these therapies really need to be initiated early, before myeloma relapse occurs,” she explained.
The big question now is what it would mean for patients if they, like the mice, got such drugs at the right time.
“The next step is to try and think about autologous transplant as a platform for undertaking a number of other immune-based therapies to try to enhance the response and stop people from eventually progressing after transplant,” Hill said. “So that’s the clinical aim now.”
Susan Keown is an associate editor at Fred Hutchinson Cancer Research Center. She has written about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at firstname.lastname@example.org or on Twitter @sejkeown.