The allogeneic stem cell or bone marrow transplant (BMT), which is used to treat certain types of blood cancer, may be one of the most rigorous cancer treatments.
The regimen that is given to patients before the transplant, known as conditioning, has many side effects, both short and long term. It involves heavy doses of chemotherapy, radiation, and antibody treatments, or some combination of the three. In addition, some patients have had months or even years of chemotherapy leading up to the transplant, resulting in further side effects.
“The purpose of conditioning is to attack the tumor cells in the patient’s bone marrow and destroy the cancer, but it also results in collateral damage to various tissues,” explains physician-scientist Marcel van den Brink, who is head of MSK’s Division of Hematologic Oncology and also has a lab in the Sloan Kettering Institute’s Immunology Program. Conditioning also destroys immune cells, including T cells, which makes the patient’s body more tolerant of the donated stem cells and less likely to attack them but also leaves the patient extremely vulnerable to infections with bacteria, viruses, fungi, and parasites.
“Because of their damaged immune systems, these patients must live like people with AIDS,” he adds. “They are susceptible to everything.”
Unfortunately, the regimen damages healthy tissues, including the kidneys, liver, lungs, and skin, and especially the gastrointestinal tract. Additional problems may also arise from the transplant. For example, immune cells from the donor may attack the patient’s healthy tissues as well, a condition known as graft-versus-host disease (GVHD).Back to top
Strategies for a Quicker Recovery
The transplant itself — in which blood stem cells or bone marrow cells from a matched donor are infused into the patient to replace cancerous cells — is actually the first part of the recovery process. MSK investigators are developing several strategies to both enable the immune system to recover more quickly after transplant and minimize organ and tissue damage from the transplant process.
“When the immune system reconstitutes itself after a transplant, the T cells are the last ones to come back,” Dr. van den Brink says. “T cells are made in an organ called the thymus, and in BMT patients the thymus is very beaten up. In addition, the thymus gets less functional as patients age, and most of our patients tend to be older.”
His lab is focused on developing ways to boost the thymus’s activity. One approach is treatment with a protein called interleukin-22 (IL-22), which is made naturally in the body by cells called innate lymphoid cells. Research done in mouse models has shown that elevated IL-22 levels can lead to an increase in the production of T cells — and potentially speed recovery of immune function.Back to top
Advancing Clinical Trials
“IL-22 also appears to be helpful in recovering the lining of the gut after transplant,” Dr. van den Brink says. “The cells in the thymus that regulate T cell development and the cells of the gut lining are both types of epithelial cells [cells that line the cavities and surfaces of the body], and IL-22 seems to help them rebuild and regenerate.” MSK recently received approval from the US Food and Drug Administration to study IL-22 in BMT patients; a trial will open in the next few months. Another interleukin protein, called IL-7, already has shown promise as a potential therapy to boost T cell regeneration in one early-stage study.
In other mouse studies, Dr. van den Brink’s lab has found that endothelial cells, which line blood and lymphatic vessels, can play an important role in regeneration of the thymus, suggesting another possible avenue for new treatments.
Finally, a trial is under way to determine whether two drugs that are already approved for other uses — either alone or in combination — may help boost the production of T cells after transplant and also reduce the incidence of GVHD in the intestinal tract. One drug is leuprolide, which is used to shut off production of sex hormones in men with advanced prostate cancer. Earlier studies have indicated that men treated with this drug have an increase in T cells.
The other drug, palifermin, is used to treat mouth sores after BMT. Palifermin stimulates epithelial cells, so it may help boost production of T cells in the thymus as well as help the gastrointestinal tract to recover more quickly.
“Infections and graft-versus-host disease are serious complications,” Dr. van den Brink says. “Our quest with all of this research is to improve patient outcomes by helping them overcome the most serious side effects of treatment.”Back to top