The preferred treatment of many high-risk or relapsed hematologic malignancies remains an allogeneic stem cell transplant. However, patients and physicians often face graft-versus-host disease (GVHD), a frequent and life-threatening complication. Miller School and Sylvester Comprehensive Cancer Center researchers have developed a method to decrease GVHD, while maintaining the benefits of T-cell virus-specific immunity.
The finding, led by senior author Krishna V. Komanduri, M.D. (pictured), Kalish Family Chair, professor of medicine and Director of the Stem Cell Transplant Program at Sylvester, and co-first authors, post-doctoral fellows Takero Shindo, M.D., Ph.D., and Tae Kon Kim, M.D., Ph.D., is published as a Plenary Paper, indicating its scientific importance.
Stem cell or bone marrow transplants provide patients with healthy T cells to fight infection. GVHD occurs when the newly transplanted cells from a donor attack the transplant recipient’s body, sensing it as foreign tissue. Physicians have used calcineurin inhibitors for decades to prevent GVHD, but by suppressing T cells indiscriminately, the patient’s immune system is weakened, increasing the risk of serious infection and also the risk of cancer relapse. The first line of therapy for GVHD is corticosteroids, which again increases the risk of infection, the leading cause of death following GVHD.
“This work addresses the critical question of how we might be able to develop more selective, and therefore safer, approaches to suppress the immune system in transplant recipients,” said Komanduri, “including those patients needing allogeneic transplants for blood cancers.”
There are different subsets of T cells: naïve T cells that have not yet encountered antigens, central memory and effector memory T cells, each marked by distinct patterns of surface markers. Alloreactive T cells, which are believed to cause GVHD, are largely contained within the pool of naïve and central memory T cells. A more differentiated effector memory T cell provides antiretroviral protection.
After finding that naïve T cells prefer to activate a specific pathway (RAS/MEK/ERK), Komanduri, Shindo, Kim, and their team, with their collaborator Robert Levy, Ph.D., professor of microbiology and immunology, hypothesized that MEK inhibitors, including selumetinib, would stop alloreactive T cells from attacking the host, while sparing the more differentiated virus-specific T cells that fight infection.
“These results suggest that a new class of drugs, currently being tested in many cancer patients, might be capable of more selective immune suppression,” said Komanduri. “We developed an approach that allowed us to suppress undesirable immune responses caused by donor cells while sparing beneficial immune responses that control infections in transplant recipients.”
Stephen D. Nimer, M.D., Director of Sylvester, said Komanduri’s findings address the most fundamental limitation of stem cell transplantation. “Dr. Komanduri’s groundbreaking research provides novel insights into a treatment strategy that could profoundly improve the success rate for patients undergoing bone marrow transplant.” He added that he expects Komanduri and his colleagues at Sylvester will be able to offer new treatment strategies to patients.
In a description of the study, Blood editors wrote that the finding “could have great potential for selective functional T-cell depletion to prevent GVHD without reducing antiviral responses.”
Komanduri said he and his team are “actively working on translating these exciting concepts to the clinic, and we hope that this will lead to trials in stem cell transplant patients and, eventually, improved clinical outcomes.”
Illustration: University of Miami.
University of Miami Health System News Release (06/18/13)
Abstract (Blood; (04/10/13))