CCR7-Depleted Allogeneic Peripheral Blood Stem Cell Product Retaining Effector Memory T Cells for Hematopoietic Transplantation

Project SummaryAbstract Despite recent advances in allogeneic stem cell transplantationgraft versus host diseaseGVHDan immunologic attack by donor cells directed against the recipientand reactivation of latent viral infections remain major sources of post transplant morbidity and mortality and limit the applicability of bone marrow transplantThe morbidity of GVHD is particularly unwelcome in non malignant conditions where elimination of the underlying disease is not dependent on immunologic rejectionGVHD is primarily mediated by T cells contained in the grafthematopoietic cells obtained from the donorwhich recognize hostrecipientantigens as being foreignStudies in mice and humans demonstrate that na ve and central memory T cellswhich may be discriminated from hematopoietic stem cells and effector memory T cells on the basis of expression of the cytokine receptor CCRare responsible for GVHDExperience over decades of allogeneic transplant demonstrates the GVHD may be avoided entirely by removing T cells or selectively transplanting only CDhematopoietic stem cells at the expense of impaired antiviral immunity resulting in life threatening reactivation of Herpes viruses and other infections which limit the overall success of the transplantThis project proposes to develop a novelfully humanizedbiotinylated antibody targeting CCRto be used with a commercial immuno magnetic bead separation deviceCliniMACSMiltenyiCambridgeMAto remove na ve and central memory T cells from allogeneic hematopoietic stem cell grafts for the purpose of preventing GVHD while preserving antiviral immunityThis application will support selection of an optimal antibody from among several fully human anti CCRantibody clones developed by MSM Protein Technologies on the basis of efficiency of target T cell depletionThe selected antibody will be produced under manufacturing conditions suitable to the FDA for use in ex vivo cell processing and in quantity sufficient to conduct future clinical scale validationThis work will enable formal application to the FDA for an investigational device exemptionIDEin support of a first in human pilot trial in patients undergoing stem transplantation for non malignant hematologic disorders including sickle cell anemia and thalassemiaThis study is submitted in response to PHSOmnibus Solicitation of the NIHDCD and FDA for Small Business Innovation Research Grant ApplicationsParent SBIRRRto NHLBI for Phase I funding Project Narrative This project will expand the application of life saving allogeneic stem cell transplantation within the community of patients with both non malignant blood disorderssickle cell anemiaaplastic anemiaand malignanciesleukemialymphomaby reducing morbidity and mortalityThe stem cell product developed will remove the cells that cause graft versus host disease while preserving those that protect against post transplant viral infections