Graft-vs-Host-Disease (GVHD) is a frequent and life-threatening complication of hematopoietic stem cell transplantation (HSCT), a procedure that often represents the best treatment option for patients suffering from hematological malignancies. Even when HLA-matched family or unrelated donors are available, an unsatisfactorily high frequency (30-40%) of transplant recipients still develop GVHD. Thus, there remains an urgent need to develop strategies to treat and prevent GVHD for patients receiving either matched or unmatched donor-recipient HSCT. Recently, CD4+FoxP3+ regulatory T cells (Tregs), which provide non-redundant function to maintain peripheral immune self-tolerance, have demonstrated potential in pre-clinical models to promote allograft acceptance. However, translation of such an approach to the clinic remains hampered by the practical and economic hurdles associated with adoptive transfer of sufficient numbers of donor Tregs to patients. In this regard, Pelican Therapeutics has developed a novel reagent that takes advantage of the natural ligand of a key receptor, TNFRSF25, expressed on Tregs. Stimulation of TNFRSF25 using a fusion protein consisting of the ligand TL1A (TL1A-Ig), in combination with IL-2, induces a dramatic and selective expansion of Tregs that effectively reduces GVHD in mice following allogeneic HSCT. These initial studies utilized a model in which Tregs were expanded in vivo with TL1A-Ig/IL-2 and then adoptively transferred to murine recipients. In this Phase I STTR, Pelican will evaluate the potential for TL1A-Ig to be directly administered to recipients undergoing HSCT, obviating the need to expand Tregs in donors prior to transplant. To verify and corroborate efficacy, two independent murine models of aHSCT will be utilized, one involving complete MHC-mismatch and an MHC- matched minor antigen-mismatched donor/recipient pair reflecting genetic disparities in clinical HSCT. In vivo effectiveness of TL1A-Ig administration for GVHD amelioration will be evaluated using established quantitative metrics that include immune phenotyping, levels of Treg expansion, analyses of immune competence and reduction in clinical signs of GVHD. Pharmacokinetics and target engagement will be characterized as part of these studies to determine suitability of TL1A-Ig as a drug candidate. To begin to translate these findings to humans, a humanized TL1A-Ig (hTL1A-Ig) reagent will be characterized first, with regard to identification of expression and kinetics of endogenous TNFRSF25 presence in human primary peripheral blood mononuclear cell (PBMC) populations. Secondly, hTL1A-Ig target engagement and downstream signaling will be examined in human PBMCs to further establish and characterize translational potential. Completion of this Phase I proof-of- concept will establish rationale for advancing this molecule into further preclinical and IND-enabling development.
Public Health Relevance Statement: NARRATIVE Every year, over 20,000 people with hematological malignancies undergo hematopoietic stem cell transplantation. A significant proportion of these patients, even among so-called “matched” donor-recipient pairs, develop graft-vs-host-disease (GVHD), a severe multi-organ inflammatory condition that often leads to patient morbidity and mortality. Pelican Therapeutics has developed a new therapeutic strategy to ameliorate GVHD in transplant recipients that utilizes their novel biomolecule, TL1A-Ig, which selectively expands tolerance-inducing regulatory T cells by targeting a key receptor.
Project Terms: Adoptive Transfer; Agonist; Allogenic; Allografting; Animals; Antigens; ANXA5 gene; Apoptosis; base; Biological Assay; Biological Markers; Blood; Bone Marrow; CASP3 gene; CD28 gene; CD3 Antigens; CD44 gene; Cell Culture Techniques; Cell Death; Cell division; cell type; Cells; Chimeric Proteins; Clinic; Clinical; clinical application; Collaborations; Complication; CTLA4 gene; Custom; cytokine; cytotoxic; Development; Diagnosis; Disease; Dose; drug candidate; Drug Kinetics; Economics; Effectiveness; Ensure; Enzyme-Linked Immunosorbent Assay; exhaustion; Family; FOXP3 gene; Frequencies; Gastrointestinal tract structure; Genetic; Graft Tolerance; graft vs host disease; Granzyme; Growth; Haplotypes; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histocompatibility Antigens; Human; Human Development; Immune; immune self tolerance; Immune signaling; Immunocompetence; improved; In Vitro; in vivo; Inflammatory; Interferon Type II; Interleukin-2; Kinetics; leukemia/lymphoma; Life; Ligands; Liver; lymph nodes; Lymphocyte; Maintenance; Mediating; Minor; Mixed Lymphocyte Culture Test; Modeling; Monitor; Monoclonal Antibodies; monocyte; Morbidity - disease rate; mortality; mouse model; Mus; novel; novel therapeutic intervention; Pathologic; Patients; Peripheral; peripheral blood; Peripheral Blood Mononuclear Cell; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Phenotype; Plasma; Population; post-transplant disease; pre-clinical; Pre-Clinical Model; prevent; Prevention; Procedures; Production; programmed cell death protein 1; programs; Prophylactic treatment; Reagent; receptor; recruit; Regulatory T-Lymphocyte; RIPK1 gene; Self Tolerance; sex; Signal Transduction; Skin; Small Business Technology Transfer Research; Spleen; success; Surface; T-Lymphocyte; Therapeutic; TNF gene; Translating; Translations; Transplant Recipients; Transplantation; Universities; Work
