Phase II year
2008
(last award dollars: 2009)
Phase II Amount
$1,131,921
Allogeneic stem cell transplantation (allo-SCT) is potentially curative therapy for a patients suffering from leukemia, lymphoma and multiple myeloma. However, the problems associated with graft-versus-host disease (GVHD) have greatly limited the use of allo-SCT to patients with either an HLA-identical family member or unrelated donor in many transplant centers. As a consequence, the development of new therapies that could prevent or treat GVHD would be a significant advance for patients needing an allo- SCT. Currently, the most common approaches to the prevention of GVHD are either a combination of S-phase active chemotherapy drugs such as methotrexate and a calcineuring inhibitor or in vivo methods of T cell depletion using antibodies such as Campath -1H. While these approaches can induce T cell tolerance, they do not impact on the generation of proinflammatory cytokines and chemokines that are induced by conditioning therapy and critical to the development of GVHD. As most new therapies for the treatment or prevention of GVHD have arisen from studies in solid organ transplantation, which does not involve inflammation-inducing conditioning therapy, we believe a new approach that focuses specifically on allo-SCT and the complications of conditioning treatment are needed for new agents to be developed. NF-(B is a dimmer composed of Rel proteins and is critical in the induction of T cell tolerance and the generation of over 200 proteins involved in inflammation. Our group has previously found that poorly soluable drugs that target NF-(B have a modest effect on the occurrence of GVHD in animal models, that is greatly limited by the bioavailability of the compound. In this proposal, we have initiated a collaboration with the biotechnology company, Theralogics, to evaluate the use of TLX1001 licensed by the company in the prevention or treatment of GVHD. This drug is an inhibitor of the catalytic domain of IKK a and blocks the activation of NF-(B by interfering with the phosphorylation of I(B. The founder of TheraLogics Al Baldwin PhD and the chief scientific officer Sankar Ghosh Ph.D. are internationally recognized experts in the biology of NF-(B. This proposal brings together two extremely experienced investigators in the biology of GVHD, in Drs Serody and Blazar, with scientists at Theralogics who are experts on the biology of NF- (B in Drs Baldwin and Ghosh and two outside experts in the pharmacology of targeted therapy in Dr. William Zamboni and dog models of GVHD in Dr. Richard Nash. Three specific aims are proposed to investigate the use of TLX1001 in the treatment of GVHD in a donor splenocyte infusion model and for the prevention of GVHD after nonmyeloablative marrow transplantation. Experiments are proposed to evaluate the combination of TLX1001 with the calcineurin inhibitor tacrolimus. Finally, studies are proposed to investigate the pharmacokinetics and pharmacodynamics of the compound in dogs after transplantation. If this phase II grant is successful, it will pave the way for clinical trials of this therapy at the University of North Carolina at Chapel Hill.
Public Health Relevance: Bone marrow or stem cell transplantation can be a life-saving procedure for individuals with certain types of blood cancers. In most instances an individual receiving a bone marrow or stem cell transplant needs to be perfectly matched with the donor for the best possible result. This is due to the fact that donor white cells can react against the proteins found on the cells of the recipient causing a disease termed graft-versus-host disease (GVHD). Even with the best possible preventative therapies, GVHD occurs in around 50% of the individuals receiving a bone marrow or stem cell transplant from a perfectly matched donor and can cause multiple complications including death of the recipient. Thus, new forms of therapy to prevent or treat GVHD are needed for the broader use of transplantation as a form of therapy. This proposal investigates a new compound that can block the white cells that cause GVHD and the proteins that cause the symptoms associated with GVHD. Experiments are proposed in animal models to test the activity of the compound and if successful the long-term goal of this work is to take this compound in human clinical trials for the treatment of GVHD.
Public Health Relevance: Project Terms: 4-Amino-10-methylfolic Acid; 4-Amino-4-deoxy-10-methylpteroyl-L-glutamic Acid; ATGN; Abbreviations; Acute GVHD; Acute Graft Versus Host Disease; Address; Adoption; Affect; Allogenic; Animal Model; Animal Models and Related Studies; Animals; Antibodies; Antigens; Approaches to prevention; B-Protein; Behavior Conditioning Therapy; Behavior Modification; Behavior Therapy; Behavior Treatment; Behavior or Life Style Modifications; Behavioral Conditioning Therapy; Behavioral Modification; Behavioral Therapy; Behavioral Treatment; Binding; Binding (Molecular Function); Bioavailability; Biologic Availability; Biological Availability; Biology; Biotechnology; Blood (Leukemia); Blood leukocyte; Bone Marrow; Bone Marrow Transplant; Bone Marrow Transplantation; Bone marrow failure; Calcineurin antagonist; Calcineurin inhibitor; Campath-1H; Canine Species; Canis familiaris; Catalase B; Catalytic Core; Catalytic Domain; Catalytic Region; Catalytic Site; Catalytic Subunit; Cells; Cessation of life; Characteristics; Ciclosporin; Clinical; Clinical Treatment; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Therapy; Clinical Trials, Unspecified; Clinical, Transplantation, Organ; Collaborations; Conditioning Therapy; Control Animal; CsA; Cyclosporin A; Cyclosporine; Cyclosporine A; Cytokines, Chemotactic; DNA-Binding Proteins; Data; Death; Development; Disease; Disorder; Doctor of Philosophy; Dogs; Drug Delivery; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug Targetings; Drugs; EC 2.7; Early-Stage Clinical Trials; Engraftment; Family; Family member; GVHD; Generations; Genes; Glucocorticoids; Glycoprotein 75; Goals; Graft-Versus-Host Disease; Graft-vs-Host Disease; Grafting Procedure; Grafting, Bone Marrow; Grant; Hematopoietic Cell Tumor; Hematopoietic Malignancies; Hematopoietic Neoplasms; Hematopoietic Neoplasms including Lymphomas; Hematopoietic Tumor; Hematopoietic and Lymphoid Cell Neoplasm; Hematopoietic and Lymphoid Neoplasms; Hematopoietic, Including Myeloma; Histocompatibility Antigens; Homologous Chemotactic Cytokines; Homologous Wasting Disease; Human; Human, General; INFLM; Immune Function, Cellular; Immune response; In Vitro; Individual; Inflammation; Infusion; Infusion procedures; Intercrines; Investigators; Kinases; L-Glutamic acid, N-(4-(((2,4-diamino-6-pteridinyl)methyl)methylamino)benzoyl)-; Lead; Leukemias, General; Leukocytes; Licensing; Life; Life Style Modification; Lymphocyte; Lymphocytic; Lymphoma, Non-Hodgkin's; Lymphoma, Nonhodgkins; Malignant Hematopoietic Neoplasm; Mammals, Dogs; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow Transplantation; Marrow leukocyte; Measures; Mediating; Medication; Methods; Methotrexate; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Mice; Minor; Modeling; Molecular Interaction; Monoclonal Antibody Campath-1H; Multiple Myeloma; Murine; Mus; Myeloma, Plasma-Cell; New Agents; Non-Hodgkin's Lymphoma; North Carolina; Nuclear; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; Pancytopenia; Patients; Pb element; Peptide Domain; Ph.D.; PhD; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Pharmacology; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phosphorylation; Phosphotransferases; Physiologic Availability; Prevention; Prevention approach; Procedures; Production; Progenitor Cell Transplantation; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Protein Domains; Protein Phosphorylation; Proteins; Relapse; Research Personnel; Researchers; Response Elements; Reticuloendothelial System, Bone Marrow; Reticuloendothelial System, Leukocytes; Runt Disease; SIS cytokines; Sandimmun; SangCya; Scientist; Signal Pathway; Solid; Specificity; Splenocyte; Stem Cell Transplantation; Stem cell transplant; Symptoms; Syndrome; T-Cell Activation; T-Cell Depletion; T-Cells; T-Lymphocyte; TRP-1; TYRP; TYRP1; TYRP1 protein, human; Tacrolimus; Tertiary Protein Structure; Testing; Therapeutic Glucocorticoid; Therapeutic Trials; Therapy Clinical Trials; Thymus-Dependent Lymphocytes; Toxic effect; Toxicities; Transphosphorylases; Transplantation; Transplantation Antigens; Transplantation Surgery; Tyrosinase-Related Protein 1; Universities; White Blood Cells; White Cell; Work; behavior intervention; behavioral intervention; bioavailability of drug; blood cancer; brown locus protein, human; canine; chemoattractant cytokine; chemokine; chemotherapy; clinical investigation; comparative efficacy; conditioning; cytokine; dimer; disease/disorder; domestic dog; drug/agent; experience; experiment; experimental research; experimental study; gene product; glycoprotein-75, human; gp75 TRP-1, brown protein, human; heavy metal Pb; heavy metal lead; host response; human TYRP1 protein; immune function; immunogen; immunoresponse; improved; in vivo; inhibitor; inhibitor/antagonist; leukemia; leukemia/lymphoma; lymph cell; lymphoma/leukemia; melanoma antigen gp75, human; member; model organism; myeloma; myelomatosis; neoral; new approaches; non-Hodgkins disease; non-Hodgkins lymphoma; novel approaches; novel strategies; novel strategy; organ allograft; organ graft; organ xenograft; phase 1 study; phase 1 trial; phase I trial; prevent; preventing; prophylactic; protocol, phase I; research study; sandimmune; thymus derived lymphocyte; transcription factor; transplant; trial regimen; trial treatment; tyrosinase-related protein 1, human; white blood cell; white blood corpuscle
