Novel Indication for Myeloid Progenitor Use: Induction of Tolerance in Solid Organ Transplantation

PROJECT SUMMARY State of the art techniques result inyear solid organ graft loss ofto overin cardiopulmonary organ transplantationEstablishment of donor specific immunological toleranceDSITa condition in which a recipient accepts a transplant without immunosuppressionwhile retaining the ability to fight infectionswould reduce graft loss and transplant related complicationsThe only identified method of inducing robust tolerance involves Hematopoietic Cell TransplantationHCTusually in the form of bone marrow transplantationBMTThough long recognized as a means of inducing DSIT that provides all tolerogenic mechanismsclinical translation has been limited due to the associated complicationsOther avenues that are currently being explored include cell therapy using immunomodulating mature hematopoietic cells such as regulatory T cellsWhile promisingthis approach may be more limited in its ability to modulate and prevent rejection responsesWe propose that progenitor cell therapyspecifically using Myeloid Progenitor cellsMPmay be the best compromise in introducing multiple immunomodulatory cell types without all the complications associated with BMTOur data to date clearly support this hypothesisWe have discovered that injection of MP can result in MP specific toleranceeven though there may be only very low level sustained MP engraftmentCellerant Therapeutics has developed a clinical MP productCLTproduced by short term ex vivo expansionMPCThese cells are currently being tested in a Phase II clinical trial aimed at preventing infections in patients undergoing chemotherapyUniquelyMPC induce robust and reproducible antigen specific tolerance in our experimental model systemare clinically availableand have been associated with minimal to no side effects in current clinical trialsMPC constitute an ideal and innovative approach in tolerance induction protocolspreferred over efforts aimed at achieving high level donor chimerismThe proposed research in phase II will focus on establishing non lethal preconditioning protocols that will work with MPC in tolerance inductionAimAimwill determine whether mixed MPC preparationsas the clinical grade cells are currently producedare effective in protecting graftsWe will also develop a xenograft mouse model to test the ability of human MPC to protect human grafts and Aimwill focus on determining the biodistribution and persistence of MPCderived cellsin order to determine critical sites and timing of tolerance inductionMeeting the milestones for these aims will set the stage for designing trials using the Cellerant MP productin which the clinical potential of this approach can be established PROJECT NARRATIVE The proposal aims to develop methods that can be used to improve the long term outcome of clinical organ transplantationsState of the art technology results in up toorgan graft loss over ten years mostly due to rejectionRe transplantation is often not possibleThe small business partner has developed an innovative productCTLMyeloid progenitorsthat can prevent infections but that can also induce specific toleranceas the academic partner has shown in preclinical modelsWe aim to transfer this technology to the small business partner for clinical development and application such that it can improve the long term outcome for patients undergoing transplantation for end stage organ failure