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 cancersFY18 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 beneficiariesBackground: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is currently the only curative treatment option for a number of hematological malignancies, however its success is limited by graft-versus-host disease (GvHD) which occurs in up to 70% of transplant recipients. Acute GvHD involves immunemediated destruction of host tissue by donor-derived allorecative T-cells and is especially prevalent in the skin, gut, and liver. GvHD is initiated by host antigen-presenting cells (APCs), which are activated in response to significant tissue damage caused by the transplant conditioning regimens used to ensure transplant engraftment. The gastrointestinal (GI) tract is especially susceptible to this damage, resulting in the breakdown of the mucosal barrier and the translocation of pro-inflammatory products. This leads to the activation of APCs and generation of a cytokine storm, creating a microenvironment that is ideal for the expansion of allorecative T-cells. As such, preserving GI mucosal integrity following conditioning and promoting enhanced barrier function represents a novel therapeutic approach to GvHD. Glucagon-like peptide-2 (GLP-2) is an enterocyte-specific growth factor that enhances bowel growth and repair and improves the mucosal barrier by reducing trans- and para-cellular permeability. These factors make GLP-2 an ideal candidate for therapeutic investigation in GvHD.Objective/Hypothesis: Using a synthetic GLP-2 analogue, elsiglutide, we will investigate the impact of pharmacological activation of the GLP-2 receptor on GvHD development in murine models. We hypothesize that the administration of elsiglutide will result in reduced susceptibility of the GI tract to chemo- and radiotherapeutic conditioning regimens. We believe that this will lead to improved mucosal barrier functions that will be reflected by in vivo permeability assays. This will in turn lead to a dampened inflammatory microenvironment, thereby reducing APC activation and the subsequent infiltration and expansion of allorecative donor cells. Combined, we hypothesize that these effects will lead to an improvement in overall survival of treated mice as well as the attenuation of GvHD severity.Specific Aims and Study DesignAim 1. Determine the impact of the GLP-2 analogue elsiglutide on prevention of high-dose chemotherapy- and radiotherapy-induced gut mucosal damage and immune activation and optimize its administration schedule. We will perform in vivo assessment of the effect of elsiglutide on gut damage induced by radio- or chemotherapeutic myeloablative conditioning in murine HSCT models. Testing various doses and administration schedules, we will use in vivo permeability assays, histological methods, and flow cytometric tools in order to assess treatment effects on damage to the GI tract and immune activation following pre-transplant conditioning.Aim 2. Investigate the therapeutic potential of the GLP-2 analogue elsiglutide in GvHD prevention and treatment in clinically relevant mouse models. Here we will examine the effect of elsiglutide in an allogeneic transplant setting using chemo- and radio therapeutic regimens. Initial experiments will center on treatment effects on overall survival (OS) and GvHD severity based on a well-established scoring criteria. This will be followed by detailed mechanistic studies investigating multi-organ tissue damage and immune activation by using an innovative single-cell transcriptoimmuno-phenotypic platform.Military Relevance: Blood cancers such as lymphoma and leukemia represent some of the more common cancer types, and their high prevalence in young adults and in children makes it highly relevant for Service men and women and their family members. Allogeneic SCT is standard therapy in blood cancers and is performed in approximately 30,000 people worldwide each year, including many military personnel.