For people with advanced blood cancers, a bone marrow transplant is often the last, best chance at a cure. But the procedure — which involves replacing diseased bone marrow with healthy blood cells from a donor — is not without risks. The most significant is graft-versus-host disease (GVHD), when donor white blood cells attack healthy tissues in the recipient. In severe cases, it can be fatal.
“Graft-versus-host disease is a complication that we’ve been battling for decades,” says Marcel van den Brink, Head of the Division of Hematologic Oncology and Co-Director of the Parker Institute for Cancer Immunotherapy at MSK. “Everybody within this field would agree that figuring out ways to limit graft-versus-host would be real progress.”
In a paper published January 9 in the journal Nature Medicine, a team of researchers led by Dr. van den Brink and Michel Sadelain, Director of the Center for Cell Engineering at MSK, present preliminary research that suggests ways to make transplants both safer and more effective.
The team is studying a type of immune cell taken from a donor and genetically modified. In a series of experiments done in mice, they showed that these altered donor cells cause less GVHD than unmodified donor cells, and deciphered the biological basis of this phenomenon. The research could lead to changes in how blood cancers are treated.
Tipping the Balance
A bone marrow transplant from a donor wipes the slate clean and gives a patient the potential for a cancer-free life with a new set of blood cells. But there’s another way the procedure heals: Because the donor immune cells are genetically different from the recipient, they can recognize any remaining cancer cells in the body as foreign and destroy them. This phenomenon — a kind of lucky side effect — is called graft-versus-tumor.
The flipside of graft-versus-tumor is when the donor immune cells attack normal tissues, causing the unwanted side effect of graft-versus-host.
“The billion-dollar question in our field is how to tip the balance between graft-versus-host and graft-versus-tumor,” says Dr. van den Brink.
One way researchers are attempting to tip this balance is by equipping immune cells with genetically modified proteins that specifically recognize targets on cancer cells and therefore enable a directed attack. These chimeric antigen receptors, or CARs, have proven remarkably successful at beating back several types of advanced leukemia in both children and adults, including acute lymphoblastic leukemia and chronic lymphocytic leukemia.
Leukemia-fighting CARs are built to recognize a marker called CD19, which is found on blood cells called B cells from which these leukemias arise. Dr. Sadelain’s group designed some of the first clinically effective CARs, and CAR T cell therapy is now being tested in clinical trials around the world.
CARs can be made from a person’s own T cells or from a donor’s. Donor T cells are used when a person relapses after a bone marrow transplant (and no longer has his or her original T cells).Back to top
A Curious Finding
According to Dr. van den Brink, about 5% of T cells from a donor contain a receptor that can recognize normal tissues and lead to GVHD. Therefore, when CAR T cells are made from donor cells, some small proportion of the modified cells will contain both types of receptor.
One might think that these dual-targeting cells would make GVHD worse by being overstimulated to go on the attack. But interestingly, recent clinical studies looking at donor-derived CAR T cells in patients who have relapsed after a BMT have found that the CAR T cells seem to cause much less GVHD than unmodified T cells.
Drs. van den Brink, Sadelain, and colleagues wanted to understand this curious finding, so they turned to a mouse model of cancer in which they could carefully tease out the mechanisms. They first made different versions of donor T cells. Into some T cells they put working CARs, specific for CD19. Into others they put sham CARs that didn’t signal. Then they tested the cells in the mice.
What they found was that donor CAR T cells that recognized both normal tissues and CD19-positive cells eventually lost their ability to function.
“Seeing both targets together leads to a cell getting too much signal over too long a period of time,” says MSK physician-scientist Scott James, who is co-first author on the paper along with fellow physician-scientists Melody Smith and Arnab Ghosh. “As a result, the cells become exhausted and eventually die.”
Since these dual-targeted cells are the ones that might have caused GVHD, the selective die-off of these cells is an unexpected boon.
Donor CAR T cells that recognized only CD19-positive cells continued to thrive and carry out their cancer-killing mission.Back to top
A New Clinical Trial
These results have immediate clinical implications. They suggest, first of all, that when a person relapses after a BMT, infusions with donor T cells modified with CARs might be safer and more effective than unmodified T cells — the current standard treatment in these patients.
Second, when using donor CAR T cells to prevent recurrence after a transplant, they suggest how these CAR T cell infusions should be timed to avoid graft-versus-host disease: They should be given once the bone marrow has recovered sufficiently such that there are plentiful CD19-positive cells in the body to help cause signal overload and exhaustion of the GVHD-causing cells.
A phase I study of using donor-derived CAR T cells to prevent relapse after BMT is being planned and is scheduled to open at MSK later this year.
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