Improving Unrelated Hematopoietic Stem Cell Transplants
The field of hematopoietic stem cell transplantation (HSCT), in which cancer patients and people with certain other diseases receive transplanted blood-producing stem cells to restore their blood and immune systems after treatment, has seen several exciting developments in recent years.
The discovery of non-bone marrow stem cell sources, including peripheral blood and fetal cord blood, has increased the supply of unrelated-donor (allogeneic) stem cells available for patients. And lower-toxicity treatment regimens - mini-transplants that merely suppress a patient's immune system before the transplant, rather than eliminate all blood-forming cells - have allowed patients who would previously have been ineligible for the procedure to receive it, including older adults and those who have comorbid conditions.
Hoping to build on these previous successes, researchers in the NCI Center for Cancer Research's Experimental Transplantation and Immunology Branch (ETIB) have launched a new initiative to explore how to optimize HSCT to maximize the benefits of the procedure while minimizing its risks.
"Our goal is to overcome the four primary barriers to HSCT: rejection, graft-versus-host-disease, tumor relapse, and lack of immune reconstitution," explains ETIB Chief Dr. Ronald Gress. The factor that influences each of these barriers most is antigen mismatching between an HSCT donor and recipient. Human leukocyte antigens are important proteins for determining this match, but other, lesser-known cell-surface proteins also play a role.
When a match is imperfect, transplanted cells can react against the recipient in what is called graft-versus-host disease, causing damage throughout the body and possible death. However, mismatched transplanted immune cells are also capable of doing what the recipient's immune system could not: recognizing and killing cancer cells. This reaction is called graft-versus-tumor effect, and with some forms of cancer, it not only restores the immune system, but actually cures the disease.
A part of this new ETIB initiative is a pilot study to look at HSCT from fully matched unrelated allogeneic donors and its potential to cure. Senior Investigator Dr. Michael Bishop and colleagues will compare two treatments that have been used in preventing graft-versus-host disease after mini-transplants: a combination of tacrolimus, methotrexate, and sirolimus; and a combination of cyclosporine and alemtuzumab.
The primary objective of the pilot study is to look at the safety of each regimen, as well as how each affects the speed of engraftment and immune reconstitution after the transplant. A secondary objective is to examine immune reconstitution using a technique known as CDR3 spectratyping, where polymerase chain reaction and gel electrophoresis are used to analyze the diversity and population of T cells against antigens.
"We're taking a personalized approach to transplantation," says Dr. Bishop. In the early days, he explains, all patients received the same transplant preparation drug doses, regardless of what treatments they had previously. "This is like using a really big hammer for every size nail," he says.
But how intact a patient's immune system is varies according to how much chemotherapy the person has received. Patients who have very weak immune systems do not need the same doses of immune-suppressing drugs as someone whose immune system is comparatively strong. T-cell number revealed by CDR3 spectratyping can guide this dosing decision, determining the competence of the rejection response in these patients.
"We can use this personalized preparation, which was developed with Dr. Dan Fowler in ETIB, to lower the immune systems only as much as is needed, so that each patient is on an equal playing field and each person has an equal chance that their graft will be successful, while sparing patients unnecessary toxicity," explains Dr. Bishop. The spectratyping can be used afterward to show how well each patient's immune system recovers.
Dr. Bishop's pilot study marks the first time that allogeneic transplants from unrelated donors are being studied by NCI at the NIH Clinical Research Center (CRC), and it will establish a platform in ETIB for future studies, including the use of cytokine-defined T-cell subsets to reduce transplant rejection and graft-versus-host disease, ways to increase function of the thymus gland to improve immune reconstitution, and new strategies to prevent and treat disease relapse.
"Unrelated transplants are being performed all over the country, but the ability to engraft cells from an unrelated donor while minimizing chemotherapy and maximizing graft-versus-tumor effect is not being tested anywhere else in this individualized way," says Dr. Gress, who notes that several other institutes at NIH have a stake in the HSCT research being performed.
—Brittany Moya del Pino