Blood: After allogeneic hematopoietic stem cell transplantation, the use of ADR receptor-expressing T cells is expected to prevent graft-versus-host disease and cancer recurrence

In a new study, researchers genetically engineered immune cells called T cells to control two life-threatening complications that typically occur after allogeneic hematopoietic stem cell transplants are treated for leukemia: graft-versus-host disease and cancer recurrence
.

In a new study, researchers from research institutions such as Baylor College of Medicine and Boston Children's Hospital genetically engineered immune cells called T cells to control allogeneic hematopoietic stem cell transplantation, which is commonly used with allogeneic hematopoietic stem cell transplantation.
allo-HSCT) treats two major life-threatening complications of leukemia: graft-vs-host disease (GvHD) and cancer recurrence
.
Their findings in animal models support further research to determine the feasibility of
using this approach to reduce mortality and improve patient outcomes.
The results 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.
"

Maksim Mamonkin, Ph.
D.
, corresponding author and assistant professor of pathology and immunology at Baylor College of Medicine, said, "In general, allo-HSCT transplantation is used to treat patients with aggressive disease who do not respond well to conventional treatment, and it has the potential to cure several types of blood cancers
.
”

Patients first receive intensive chemotherapy to eliminate most of their cancer, but this also severely damages the immune system and hematopoietic cells
.
To save these vital functions, the patient receives an inffusion of hematopoietic stem cells from a healthy donor, which populate the patient's body and restore the normal hematopoietic process
.

Hematopoietic stem cells used for transplantation typically contain small numbers of donor immune cells called T cells, which recognize the recipient's normal organs and tissues as foreign and initiate a process similar to immune rejection, causing graft-versus-host disease (GvHD).

"This is a very serious complication that requires aggressive immunosuppression to stop these T cells to prevent them from causing organ failure and death
," Mamonkin said.
”

However, immunosuppressive drugs also hamper a patient's ability to fight infections and cancer, and sometimes do not stop GvHD
.
"As a result, cancer recurrence and GvHD are the leading causes of
death in patients after hematopoietic stem cell transplantation," Mamonkin said.
This prompted us to be interested in
finding alternatives to treat GVHD and tumor recurrence.
”

Mamonkin and his research team hope to protect patients from GvHD and cancer recurrence without eliminating their normal immunity, which helps fight leukemia, but also from serious disease-causing viral infections such as cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus, which often emerge
after these vulnerable patients receive hematopoietic stem cell transplants.

The team has extensive experience
in developing engineered T cell therapies against malignant T cells, such as T-cell leukemia and lymphoma, and testing these approaches clinically.
Targeting T cells that cause GvHD seems like a logical extension of
their previous work.

Mamonkin explains, "Our goal 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, we need to find a way to identify these cells as --- a marker expressed primarily on the surface of T cells mediating GvHD rather than in other cells
.
After extensive searching, we found that the protein OX40 is a promising candidate marker
.
”

To validate this target protein, the team contacted collaborators from Boston Children's Hospital studying GvHD in a nonhuman primate model
.
They confirmed that OX40 was abundant
on the surface of T cells infiltrated into the target organ of macaques during acute GvHD.

The authors then engineered a receptor called the alloimmune defense receptor (ADR) to be expressed on the surface of therapeutic T cells, allowing them to recognize and kill T cells
expressing the OX40 protein.

Tests with therapeutic T cells in laboratory and animal models have shown that ADR-expressing T cells (hereinafter referred to as ADR T cells) are very effective at inhibiting T cells mediating GvHD and protecting animals from this fatal complication
.
At the same time, Mamonkin said, ADR T cells did not cause much damage to the "good" T cells that controlled viral infection, "leading us to believe that this therapy generally does not have an immunosuppressive effect.
"

Inspired by these findings, the team combined ADR and chimeric antigen receptor (CAR), which specifically recognizes leukemia, into T cells to test whether these T cells, which express both ADR and CAR, can 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, paving the way
for testing this approach in patients at high risk of both complications.

Mamonkin said, "We successfully genetically engineered T cells from healthy donors to prevent both complications
after bone marrow transplantation.
" We are pleased to further evaluate the value of this approach in the treatment of aggressive blood cancers and ultimately improve the clinical outcomes
of patients following hematopoietic stem cell transplantation.
" (Bio Valley Bioon.
com)

Resources:

Feiyan Mo et al.
Engineering T cells to suppress acute GvHD and leukemia relapse after allogeneic hematopoietic stem cell transplantation.
Blood, 2022, doi:10.
1182/blood.
2022016052.