In a recent study, researchers from Baylor College of Medicine and Boston Children’s Hospital, among other institutions, genetically modified T cells to control two major life-threatening complications, graft-vs-host disease (GvHD) and cancer recurrence, which usually occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Their findings in animal models support further studies to determine the feasibility of using this approach to reduce mortality and improve patient prognosis. The findings were recently published in the journal Blood in a paper titled “Engineering T cells to suppress acute GvHD and leukemia relapse after allogeneic hematopoietic stem cell transplantation”.
Dr. Maksim Mamonkin, the corresponding author of the paper and Assistant Professor of Pathology and Immunology at Baylor College of Medicine, introduced that in general, allo-HSCT transplantation is used to treat patients with aggressive disease that does not respond well to conventional therapy, and it has the potential to cure several types of blood cancers.
For general tumor treatment, patients first receive intensive chemotherapy that eliminates most of tumor cells, but this also severely damages the immune system and blood-forming cells. To salvage these vital functions, patients receive transfusions of hematopoietic stem cells from healthy donors that populate the patient’s body and restore normal hematopoietic processes.
The hematopoietic stem cells used for transplantation usually contain small amounts of donor T cells, which recognize the recipient’s normal organs and tissues as foreign and initiate an immune rejection-like process that causes GvHD. Dr. Mamonkin said, “This is a very serious condition that requires aggressive immunosuppression to stop these T cells on their tracks, to prevent them from causing organ failure and death.”
However, immunosuppressive drugs also hinder the patient’s ability to fight infection and cancer and sometimes do not stop GvHD. As a result, cancer recurrence and GvHD are the leading causes of death in several patients after hematopoietic stem cell transplantation, which prompted the interest of the research team in finding alternative options for treating GVHD and tumor recurrence.
Dr. Mamonkin and his research team hope to protect patients from GvHD and cancer recurrence without eliminating their normal immunity, thus not only helping patients fight leukemia but also protecting them from serious disease-causing viral infections such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus, which often occur in these vulnerable patients who receive hematopoietic stem cell transplantation.
The team has extensive experience in developing engineered T-cell therapies targeting malignant T cells such as T-cell leukemia and lymphoma, and in testing these approaches in the clinic. Using a similar strategy for targeting T cells that cause GvHD seemed like a logical extension of their previous research work.
The goal of Dr. Mamonkin’s research team is to selectively remove the T cells that cause GvHD to occur while preserving the body’s ability to fight other diseases. To do this, they tried to find a way to identify these cells, a marker that is expressed primarily on the surface of T cells that mediate GvHD and not in other cells. After an extensive search, They found the protein OX40 to be a promising candidate marker.
To validate this target protein, the team contacted collaborators from Boston Children’s Hospital who have studied GvHD in non-human primate models. They confirmed that OX40 is abundantly present on the surface of T cells that infiltrate into macaque target organs during acute GvHD.
These authors then engineered a receptor called the alloimmune defense receptor (ADR) to be expressed on the surface of therapeutic T cells, thereby enabling them to recognize and kill T cells expressing the OX40 protein.
Tests with therapeutic T cells in the laboratory and in animal models have shown that ADR-expressing T cells very effectively suppress T cells that mediate GvHD and protect animals from this deadly complication. At the same time, Dr. Mamonkin claimed the ADR T cells did not cause much damage to the “good” T cells that control viral infections, which means that this therapy is not generally immunosuppressive.
Inspired by these findings, the team combined ADR and chimeric antigen receptor (CAR), which specifically recognizes leukemia, to T cells to test whether these T cells expressing both ADR and CAR could fight GvHD and cancer recurrence after hematopoietic stem cell transplantation. In fact, T cells expressing both ADR and CAR protected the animals from GvHD and leukemia recurrence, thus paving the way for testing this approach in patients at high risk for both complications.
Reference
1. Mo, Feiyan, et al. “Engineering T cells to suppress acute GVHD and leukemia relapse after allogeneic hematopoietic stem cell transplantation.” Blood, The Journal of the American Society of Hematology 141.10 (2023): 1194-1208.