Anew conditioning regimen may prevent the deadly complication of graft-versus-host disease in patients receiving hematopoietic cell transplantation from an unrelated donor.
Proceedings of the National Academy of Sciences recently published the findings from Defu Zeng, Ph.D., and his City of Hope colleagues online.
The procedure could expand the use of hematopoietic cell transplantation, or HCT, to treat autoimmune diseases such as lupus and type 1 diabetes — as well as among more patients with hematologic cancers.
Graft-versus-host disease, or GVHD, is among the most common — and potentially lethal — side effects for patients undergoing allogeneic HCT with total body irradiation or high-dose chemotherapy before transplantation. In allogeneic HCT, hematopoietic stem cells come from another donor, rather than the patient.
In GVHD, donated immune cells attack the patient’s own tissues and organs as foreign.
“We have developed a radiation-free, GVHD-preventive regimen that potentially can promote the application of allogeneic HCT for the cure of hematological cancers and autoimmune diseases,” said Zeng, principal investigator and assistant professor in City of Hope’s Department of Diabetes & Endocrinology and Division of Hematology & Hematopoietic Cell Transplantation.
The conditioning regimen has two parts. The first uses the antibody anti-CD3 to target and kill the patient’s T-cells, which would otherwise attack donated bone marrow — and it does this without damaging the patient’s other tissue. The second part uses the epigenetic drug vorinostat to kill cancer cells — as well as residual anti-CD3-activated host T-cells — and reduce the side effects of the anti-CD3 infusion.
Unlike traditional chemotherapies, which cause the body’s tissues to release inflammatory chemicals that spur GVHD, vorinostat actually can keep tissues from releasing these chemicals. That helps the combination of anti-CD3 and vorinostat prevent GVHD.
The treatment also has implications for autoimmune disorders, such as lupus.
Physicians have seen that HCT has the potential to help autoimmune disorders that do not respond to other treatment, but the toxicity of radiation and chemotherapy and the possibility of GVHD have prevented HCT’s use. The new regimen may change that.
In addition to Zeng, City of Hope study collaborators included Nainong Li, M.D., Ph.D., Dongchang Zhao, M.D., Ph.D., and other lab members, together with Mark Kirschbaum, M.D., Tim Nesvig Lymphoma Fellow and director of new drug development in the Division of Medical Oncology & Therapeutics Research. Zeng also acknowledged the support of Fouad Kandeel, M.D., director of the Department of Diabetes and Endocrinology, and Stephen Forman, M.D., Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation. Forman and Kirschbaum are developing the clinical trial.
The research was backed by the Marcus Foundation, a gift from Lynn Davis — an enthusiastic supporter of research into treating autoimmune diseases with HCT — and a pilot grant from the Lymphoma Specialized Program of Research Excellence, led by Forman.
