Glucagonlike Peptide 2 (GLP-2) Analogues as a Novel Strategy for Prevention and Treatment of Graft-Versus-Host Disease

Fiscal Year 2018 (FY18) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: Immunotherapy, Blood cancers

FY18 PRCRP Military Relevance Focus Area: Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries

Allogeneic stem-cell transplantation (SCT), a procedure in which bone marrow stem cells and immune cells are transferred from a donor to a recipient, is performed in 30,000 patients with blood cancers each year, including many active duty Service men and women. Allogeneic SCT is the oldest form of cancer immunotherapy, in which the donor's immune system is harnessed to attack and destroy the recipient's cancer cells, a process known as the graft-versus-tumor (GvT) response. Graft-versus-host disease (GvHD) is one of the most common complications of allogeneic SCT, when the donor immune system targets normal recipient organs and causes severe inflammation and damage, primarily in skin, liver, and gut. GvHD can be life threatening, and requires aggressive therapy with drugs that suppress the immune system, leading to infections, cancer relapse, and poor quality of life. GvHD is the most frequent cause for treatment-related death after SCT. The current approach to prevention is only partially effective with 30% to 70% of transplant patients still encountering significant GvHD. Better strategies that prevent or treat GvHD efficiently without suppressing the immune system are a major unmet need, and their development will allow us to extend allogeneic SCT to older and sicker patients who are currently ineligible for this procedure due to this devastating complication.

GvHD is caused by donor lymphocytes, specifically T-cells, which identify recipient tissues as foreign and attack them. T-cells, however, are not able to spontaneously attack these tissues and require activation in the form of 'antigen priming.' Here, recipient cells known as antigen presenting cells (APCs) uptake elements from damaged organs and, as their name suggests, present them to T-cells that recognize that tissue as foreign. In the right setting, such as a highly inflamed and damaged tissue, the APCs also co-present stimulatory molecules, which serve as a second signal, giving the T-cells a green-light to undergo massive expansion and infiltration into host organs. Attenuating APC activation therefore presents an ideal therapeutic target, as this would limit their ability to stimulate the GvHD-causing T-cells.

A major component contributing to APC activation is the damage caused by the chemotherapy or radiotherapy used as a part of the transplantation process, particularly within the gastrointestinal tract. This damage breaks down the intestinal barrier and leads to the exposure of APCs to highly pro-inflammatory bacterial products that are naturally present in the gut, further exacerbating their capacity to stimulate GvHD-causing cells. Therefore, we hypothesize that limiting this damage to the GI tract and enhancing its repair mechanisms will dampen immune-activation and prevent the development of GvHD.

Glucagon-like peptide-2 (GLP-2) is a naturally produced intestinal protein that promotes bowel growth, prevents cell death, and improves the barrier that prevents microbial products from entering the system. There is also evidence to suggest that it has anti-inflammatory properties and several synthetic versions of the protein are commercially available, including the Food and Drug Administration-approved drug teduglutide. Taken together, these factors make GLP-2 an ideal therapeutic candidate to study for GvHD. As such, we plan to investigate the ability of the GLP- 2 analogue elsiglutide to treat and prevent GvHD in mouse models.

This strategy is ultimately designed to mitigate the toxicity of allogeneic SCT, reduce the number of patients who die or become severely ill after transplantation, and therefore extend its applicability to a greater number of patients with a larger variety of diseases. Of the 8,000 allogeneic SCT procedures conducted each year in the United States, a significant proportion is done in Service personnel or their beneficiaries. If this proposal is successful and leads to advancement in the efficacy or safety of SCT the procedure could be extended to older individuals who are currently ineligible, an occurrence that is frequent in aging Veterans. Finally, SCT is the only current treatment for severe radiation damage, therefore any treatment that can improve GvHD outcomes has extreme military relevance considering the higher risk of exposure to our Service personal as global nuclearization becomes an increasing threat.