Researchers Identify Strategy for Reducing Risk of Acute Graft-Versus-Host Disease for Many With Blood Cancers

Roswell Park/University of Minnesota study proposes new way to improve outcomes following stem cell transplant

BUFFALO, N.Y. — Preclinical research from Roswell Park Comprehensive Cancer Center and the University of Minnesota demonstrates that inhibiting a particular metabolic pathway decreases the incidence and severity of a serious side effect, acute graft-versus-host disease, while preserving beneficial effects of treatment for cancer patients who receive an allogeneic hematopoietic stem cell transplant. The findings from this early-stage research outline a new strategy for limiting side effects and improving outcomes for people who undergo stem cell transplant as treatment for blood cancer.

Newly published in JCI Insight, the study was led by Saeed Daneshmandi, PhD, Research Assistant Professor of Oncology at Roswell Park, and Eun Ko, a doctoral candidate at the University of Minnesota, in collaboration with Philip McCarthy, MD, Director Emeritus of the Transplant & Cellular Therapy Center at Roswell Park; Hemn Mohammadpour, DVM, PhD, Assistant Professor in Roswell Park’s Department of Cell Stress Biology; and Bruce Blazar, MD, Regents Professor of Pediatrics at the University of Minnesota Medical School.

Graft-versus host disease (GvHD) is a potentially fatal side effect of allogeneic hematopoietic stem cell transplant (allo-HSCT), which involves transplanting healthy donor blood and marrow stem cells into patients with leukemia, lymphoma and other blood cancers and disorders. It occurs when some of the donor’s immune cells, called alloreactive T cells, recognize the patient’s normal cells as foreign and attack them. Reducing the risk of GVHD without diminishing the donor cells’ power to kill cancer cells presents a major challenge.

The research team found that alloreactive T cells cannot multiply and fully develop without the pentose phosphate pathway (PPP). They used the pentose phosphate pathway inhibitor 6-aminonicotinamide (6AN) to block that pathway and “rewire” the metabolism of these T cells, revealing the potential of the PPP as a therapeutic target. In preclinical models, the strategy reduced the severity of acute GvHD (aGvHD), preserved the beneficial graft-versus-tumor (GvT) effect and generated effector T cells that produced the cancer-killing protein granzyme B.

“This approach could improve outcomes and decrease the toxicity of allogeneic hematopoietic stem cell transplant,” says Dr. McCarthy.

Every year more than 8,000 patients in the U.S. undergo allogeneic HCT for the treatment of leukemia, lymphoma and other blood cancers. GvHD is a leading cause of death and unfavorable outcomes in those patients.