ASH 2011: Over-expression of TRAIL on donor T-cells enhances GVT and suppresses GVHD

12 Dec 2011
ASH 2011: Over-expression of TRAIL on donor T-cells enhances GVT and suppresses GVHD

Scientists have discovered a method of using genetically engineered T-cells to help the body kill cancer cells more effectively without causing a deadly post-transplant complication.

One of the reasons cancer cells are able to grow, multiply, and spread so quickly is that the body recognizes them as normal, rather than diseased. Patients with blood cancers often receive a transplant of healthy hematopoietic, or blood-forming, stem cells to help attack cancer cells, called hematopoietic cell transplantation(HCT).

When these immune system cells found in the bone marrow are transplanted from a healthy donor to a cancer patient, donor cells may recognize the cancer cells in the recipient’s body and attack them, a desirable phenomenon known as the graft-versus-tumor (GVT) effect.

However, one of the challenges of HCT is the risk for graft-versus-host disease (GVHD), a serious and often deadly post-transplant complication which occurs when the donor cells attack the recipient’s healthy cells instead.

To combat GVHD, doctors administer powerful medications to suppress the immune system. While these medications reduce the probability of GVHD, they can also reduce the GVT effect. Recognizing this challenge, researchers sought to create a new method to suppress GVHD without compromising the GVT effect by using genetically engineered donor T-cells that over-express a protein known to induce cell death in an effort to specifically attack cancer cells.

The protein, Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand, or TRAIL, is naturally expressed on some immune cells in the body. TRAIL targets tumor cells and keeps them from multiplying and spreading by interacting with death receptor molecules, which are highly expressed on the surface of tumor cells, making them more susceptible to therapeutic targeting using TRAIL.

To evaluate the effect of genetically engineered donor T-cells over-expressing TRAIL (TRAIL+) on GVHD and GVT, investigators from Memorial Sloan-Kettering Cancer Center performed HCT using TRAIL+ donor T-cells versus control donor T-cells in experimental mouse models with cancerous tumors. Mice that received TRAIL+ donor T-cells displayed significantly higher survival rates, indicating greater antitumor activity than in those treated with control donor T-cells.

The researchers also used donor TRAIL+ progenitor T-cell with autologous (stem cells from the patient) HCT in tumor-bearing mice and found a significantly higher anti-tumor effect compared with controls. In addition to enhanced GVT effect, the transplant recipients treated with TRAIL+ T-cells experienced significantly less severe GVHD.

Researchers further found that the immune cells, which trigger GVHD, also express TRAIL-sensitive death receptors, and TRAIL+ T-cells can suppress GVHD by targeting these cells.

“Our data show that donor T-cells over-expressing TRAIL can suppress GVHD while simultaneously enhancing the GVT effects.

We hope this approach will provide fresh insights into separating cancer cell killing from indiscriminate killing of normal tissues,” said Arnab Ghosh, MD, PhD, lead author and a Research Scholar in the laboratory of Dr. Marcel van den Brink at Memorial Sloan-Kettering Cancer Center in New York. “Furthermore, the ability to combine genetic engineering with T-cell progenitor cells highlights the possibilities of developing these approaches into an effective, ‘off the shelf’ cell therapy.”