SBIR-STTR Award

State of the art techniques result in 10-year solid organ graft loss of up to 80% in cardiopulmonary organ transplantation, and re-transplantation is often not possible. Establishment of donor-specific immunological tolerance (DSIT), a condition in which a recipient accepts a transplant without immunosuppression, while retaining the ability to fight infections, would reduce graft loss. The only identified method of inducing robust tolerance involves Hematopoietic Cell Transplantation (HCT), usually in the form of bone marrow transplantation (BMT). Though long recognized experimentally as a means of inducing DSIT, clinical translation has been limited due to the associated complications. A major problem has been the treatment necessary to prepare a recipient for a blood cell transplant. White blood cell counts fall precipitously, resulting in neutropenia and increased susceptibility to infections To reduce infections associated with neutropenia in HCT recipients, unrelated myeloid progenitors (MP) can be injected together with the HCT. This therapy is effective in the laboratory setting in reducing deaths caused by bacterial and fungal infections, and several trials testing a clinical MP product developed by Cellerant Therapeutics (CLT-008) MP in humans are ongoing. We have discovered that injection of MP under these conditions results in MP-specific tolerance, even though there may be only very low-level MP engraftment after the first month. Important, MP from B10;B6-Rag2-/-Il2rg- /- mice, which are incapable of producing functional B, T or NK cells, induce tolerance and clearly show that organ graft-matched lymphoid cells are not essential under these conditions. Uniquely, MP cells induce antigen-specific tolerance in our experimental model system, are clinically available, and have been associated with minimal to no side effects in current clinical trials. MP constitute an ideal and innovative approach in tolerance induction protocols, preferred over efforts aimed at achieving high level donor chimerism. The proposed research in phase I will focus on (Aim 1) testing whether MP can prevent specific lung transplant rejection symptoms, important because lung transplants may be a good patient population for initial trials and (Aim 2) on testing the degree of mismatch allowed between MP and organ graft, as this will affect the production of clinical grade MP for clinical tolerance trils. The design of these trials using a Cellerant produced clinical MP product would be the next stage following this STTR project.

Public Health Relevance Statement:


Public Health Relevance:
The proposal aims to develop methods that can be used to improve the long-term outcome of clinical organ transplantations. State of the art technology results in up to 80% organ graft loss over ten years mostly due to rejection, and re-transplantation is often not possible. The academic partner has developed preclinical tolerance models and has shown that myeloid cells can induce specific tolerance. The small business partner is currently studying an innovative product (CTL-008, human Myeloid Progenitor Cells) in clinical trials for the prevention of infections. Together we are aiming to test if a commercial Myeloid Progenitor Cell product for the induction of tolerance in solid organ transplantation is feasible and to transfer this technology to the small business partner for further clinical development and application such that it can improve the long-term outcome for patients undergoing transplantation for end-stage organ failure.

Project Terms:
Adverse effects; Affect; Allogenic; Allografting; Antigens; Autologous; B-Lymphocytes; Bacterial Infections; base; Biological Models; Blood Cells; body system; Bone Marrow; Bone Marrow Transplantation; Bronchiolitis; Businesses; Cardiopulmonary; Cause of Death; Cell physiology; Cell Transplants; Cells; Child; Chimerism; Cities; Clinical; clinical application; Clinical Protocols; Clinical Trials; Clinical Trials Design; clinically relevant; Development; efficacy testing; end-stage organ failure; Engraftment; Epithelium; Experimental Models; Failure (biologic function); falls; fighting; Goals; Graft Rejection; Graft Survival; Heart Transplantation; hematopoietic cell transplantation; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; High Dose Chemotherapy; Human; Immunocompetent; improved; Infection; Infection prevention; Infusion procedures; Injection of therapeutic agent; innovation; Interleukin Receptor; Kansas; Laboratories; Lead; Lesion; leukemia; Longevity; Lung; Lung Transplantation; Lymphocyte; Lymphoid Cell; Maintenance; Methods; Minor; Missouri; Modeling; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; Mycoses; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Natural immunosuppression; Natural Killer Cells; Neutropenia; novel; novel strategies; Organ; Organ Transplantation; Outcome; patient population; Patients; Phase; Population; pre-clinical; Pre-Clinical Model; preconditioning; Predisposition; prevent; Production; progenitor; Protocols documentation; public health relevance; Quality of life; recombinase; Regimen; Research; Respiratory physiology; Severities; Signal Transduction; Small Business Technology Transfer Research; Solid; Staging; success; Survival Rate; Symptoms; T-Lymphocyte; Techniques; Technology; Technology Transfer; Testing; Therapeutic; Time; Translating; Translational Research; Translations; Transplant Recipients; Transplantation; Umbilical Cord Blood Transplantation; University Hospitals; White Blood Cell Count procedure

State of the art techniques result in 10-year solid organ graft loss of 50 to over 70% in cardiopulmonary organ transplantation. Establishment of donor-specific immunological tolerance (DSIT), a condition in which a recipient accepts a transplant without immunosuppression, while retaining the ability to fight infections, would reduce graft loss and transplant related complications. The only identified method of inducing robust tolerance involves Hematopoietic Cell Transplantation (HCT), usually in the form of bone marrow transplantation (BMT). Though long recognized as a means of inducing DSIT that provides all tolerogenic mechanisms, clinical translation has been limited due to the associated complications. Other avenues that are currently being explored include cell therapy using immunomodulating mature hematopoietic cells such as regulatory T cells. While promising, this approach may be more limited in its ability to modulate and prevent rejection responses. We propose that progenitor cell therapy, specifically using Myeloid Progenitor cells (MP) may be the best compromise in introducing multiple immunomodulatory cell types without all the complications associated with BMT. Our data to date clearly support this hypothesis. We have discovered that injection of MP can result in MP-specific tolerance, even though there may be only very low-level sustained MP engraftment. Cellerant Therapeutics has developed a clinical MP product (CLT-008) produced by short-term ex vivo expansion (MPC). These cells are currently being tested in a Phase II clinical trial aimed at preventing infections in patients undergoing chemotherapy. Uniquely, MPC induce robust and reproducible antigen-specific tolerance in our experimental model system, are clinically available, and have been associated with minimal to no side effects in current clinical trials. MPC constitute an ideal and innovative approach in tolerance induction protocols, preferred over efforts aimed at achieving high-level donor chimerism. The proposed research in phase II will focus on establishing non-lethal preconditioning protocols that will work with MPC in tolerance induction (Aim 1). Aim 2 will determine whether mixed MPC preparations, as the clinical grade cells are currently produced, are effective in protecting grafts. We will also develop a xenograft mouse model to test the ability of human MPC to protect human grafts and Aim 3 will focus on determining the biodistribution and persistence of MPC (derived cells) in order to determine critical sites and timing of tolerance induction. Meeting the milestones for these aims will set the stage for designing trials using the Cellerant MP product, in which the clinical potential of this approach can be established.

Public Health Relevance Statement:
PROJECT NARRATIVE The proposal aims to develop methods that can be used to improve the long-term outcome of clinical organ transplantations. State of the art technology results in up to 80% organ graft loss over ten years mostly due to rejection. Re-transplantation is often not possible. The small business partner has developed an innovative product (CTL-008, Myeloid progenitors) that can prevent infections but that can also induce specific tolerance, as the academic partner has shown in preclinical models, We 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.

NIH Spending Category:
Biotechnology; Hematology; Organ Transplantation; Prevention; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human; Transplantation

Project Terms:
Ablation; academic minor; Acute Myelocytic Leukemia; Adverse effects; Alleles; Allogeneic Bone Marrow Transplantation; Allogenic; Antigens; Autologous; Biodistribution; Biological Models; Bone Marrow Transplantation; Businesses; Cardiopulmonary; Cell physiology; Cell Therapy; cell type; Cells; Cellular Structures; chemotherapy; Child; Chimerism; Chronic; Cities; Clinic; Clinical; clinical application; clinical development; clinical practice; Clinical Protocols; clinical translation; Clinical Trials; clinically relevant; Data; end-stage organ failure; Experimental Models; fighting; Funding; Goals; Graft Rejection; Graft Survival; Haplotypes; Heart; Hematopoietic; hematopoietic cell transplantation; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immune Tolerance; Immunocompetent; immunoregulation; Immunosuppression; improved; Individual; Infection; Infection prevention; Injections; innovation; Kansas; Liver; Longevity; Lung; Lung Transplantation; Mediating; meetings; Methods; Missouri; Modeling; Morbidity - disease rate; mortality; mouse model; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; novel; Organ; Organ Transplantation; Outcome; Patient-Focused Outcomes; Patients; Phase; Phase II Clinical Trials; Population; Pre-Clinical Model; preconditioning; Preparation; prevent; progenitor; Progenitor Cell Engraftment; Protocols documentation; Quality of life; Regulatory T-Lymphocyte; Reproducibility; Research; response; Site; Skin; Skin graft; Small Intestines; Solid; Stem cells; Survival Rate; Techniques; Technology; Technology Transfer; Testing; Therapeutic; Time; Trachea; Translating; Translational Research; transplant model; Transplantation; trial design; University Hospitals; Work; Xenograft procedure