Allogeneic Regulatory Dendritic Cell (DCreg) Renal Study

Study Overview
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Brief Summary
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This study will evaluate the safety and feasibility of treatment involving a single infusion of donor-derived regulatory dendritic cells (DCreg) in first time, living donor renal transplant recipients. DCreg will be prepared from monocytes obtained by leukapheresis from prospective (non-mobilized) living kidney donors and infused into the respective recipients 7 days before renal transplantation. This study will enroll 28 subjects (14 recipients, 14 donors). The duration of follow-up will be: 1 week following the leukapheresis procedure for donors and 2 years following their DCreg infusion for kidney recipients.

Detailed Description
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This clinical trial is a single-center, open-label, dose-escalation, phase 1 study, enrolling N=14 de novo kidney transplant recipients and their respective living donors. The study objective is to evaluate the safety and feasibility of a single infusion of donor-derived regulatory dendritic cell (DCreg) treatment. Transplant recipients will receive combination immunosuppressive agents according to the site's Standard of Care (SOC) regimen, with two exceptions: mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and the pre-transplant dose of MPA will be half the standard post-transplant dose, due to increased drug bioavailability in recipients with low kidney function defined by glomerular filtration rate (GFR). Consequently, participants will be maintained on triple immunosuppressive therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide. Note: Participants will not be withdrawn from known effective therapy for the purpose of participating in this research.

Official Title
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Allogeneic Regulatory Dendritic Cell (DCreg) Therapy in Live-Donor Renal Transplant Recipients

Conditions
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Kidney Transplant, Renal Transplant Recipients

Intervention / Treatment
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* Biological: DCreg: 0.5 million cells/kg+SOC
* Biological: DCreg: 1.2 million cells/kg+SOC
* Biological: DCreg:2.5 to 5.0 million cells/kg+SOC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Donor Eligibility Criteria: Able to understand and provide informed consent; Meets all standard institutional criteria for kidney donation and Health Agency compliance with kidney donation regulations; For females of childbearing potential, a negative urine or serum pregnancy test; Negative for tuberculosis by either a negative: Purified Protein Derivative (PPD) test or Result using an approved interferon-gamma release assay (IGRA) blood test, such as QuantiFERON®-Gold TB or T-SPOT.TB assay, Unless the participant has completed treatment for latent tuberculosis, and has a negative chest x-ray. Note: PPD or IGRA testing documented to have been performed within 52 weeks before transplant is acceptable Prior recipients of a Bacille Calmette-Guérin (BCG) vaccination must follow the same requirements Negative for Human Immunodeficiency Virus type 1 (HIV) -1 (antigen and Nucleic Acid Testing (NAT)), HIV-2, Human T-cell leukemia virus type 1 (HTLV-1), and HTLV-2; Negative for hepatitis C (antibody and NAT), hepatitis B (surface antigen and core antibody), and Treponema pallidum infection; Negative for West Nile Virus; Negative health history for risk factors related to Zika Virus and Creutzfeldt-Jakob disease; No live vaccines within 8 weeks prior to leukapheresis; No medical condition(s) that the investigator deems incompatible with participation in the trial; and No use of investigational drugs within 12 weeks of participation. Recipient Inclusion Criteria: Must be able to understand and provide informed consent; Is undergoing first living donor renal transplant; For females of childbearing potential, a negative urine or serum pregnancy test upon study entry and agreement to use effective contraception according to Health Agency oversight standards throughout the interval of study participation; Cytomegalovirus (CMV) seropositive or, if CMV seronegative must be receiving a kidney from a CMV seronegative donor; Negative for tuberculosis by either negative: Purified Protein Derivative (PPD) test or Result using an approved interferon-gamma release assay (IGRA) blood test, such as QuantiFERON®-Gold TB or T-SPOT.TB assay. Exception: If the participant has completed treatment for latent tuberculosis, and has a negative chest x-ray. Note: PPD or IGRA testing documented to have been performed within 52 weeks before transplant is acceptable. Prior recipients of a Bacille Calmette-Guérin (BCG) vaccination must follow the same requirements as referenced above. And meets all standard institutional criteria for kidney transplant. Study Exclusion Criteria: Panel Reactive Antibody (PRA >20%); Positive T or B Cell Flow Crossmatch prior to transplant; Presence of donor specific antibody (DSA) ≥ to mean fluorescence intensity (MFI) of 1000, or DSA between 500 and 1000, if a specific shared epitope pattern is present; Recipient of multi-organ transplant; Any prior renal or extra-renal transplant; Epstein-Barr Virus (EBV) Immunoglobulin G (IgG) seronegative status; Seropositivity for HIV-1, hepatitis B core antigen, or hepatitis C virus (HCV) antibody (if hepatitis C antibody positive, confirm negative infection by HCV RNA), or positivity for hepatitis B surface antigen; History of malignancy other than non-melanomatous skin cancer; High risk for recurrence of renal disease: Hemolytic Uremic Syndrome Thrombotic Thrombocytopenic Purpura (HUS-TTP), Focal Segmental Glomerular Sclerosis (FSGS), or Aggressive native kidney disease. Significant coronary artery disease, Ejection Fraction <30% or prior acute myocardial infarction; Compensated and decompensated cirrhosis of liver and/or portal hypertension; Chronic Obstructive Pulmonary Disease requiring nasal oxygen, and/or pulmonary hypertension (mean pulmonary pressure >45mm/hg); Any history of stroke with neurological deficit; Any condition that, in the opinion of the investigator, confers excessive risk for participation in this phase 1 study; Presence of a condition that requires treatment with an immunosuppressive agent, other than a physiologic dose of corticosteroid; Live vaccines within 8 weeks prior to transplant; Use of investigational drugs within 12 weeks of participation; Women receiving a kidney from a man who has fathered her child(ren), whether or not carried to term; or Women receiving a kidney from her biological child.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Open-label, dose-escalation, phase 1 clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DCreg: 0.5 million cells/kg+SOC<br>N=3 participants will receive 0.5 (± 0.1) million cells/kg body weight as a single infusion. Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions: mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR). Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide. | Biological: DCreg: 0.5 million cells/kg+SOC<br>* DCreg 0.5 (±0.1) million cells/kilogram body weight infused as a single dose. Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions: mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR). Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.<br>* Other names: Regulatory Donor-Derived Dendritic Cells (DCreg);|
| Experimental: DCreg: 1.2 million cells/kg+SOC<br>N=3 participants will receive 1.2 (± 0.2) million cells/kg body weight as a single infusion. Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions: mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR). Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide. | Biological: DCreg: 1.2 million cells/kg+SOC<br>* DCreg 1.2 (±02) million cells/kilogram body weight infused as a single dose. Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions: mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR). Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.<br>* Other names: Regulatory Donor-Derived Dendritic Cells (DCreg);|
| Experimental: DCreg:2.5 to 5.0 million cells/kg+SOC<br>N=8 participants will receive 25 to 5.0 million cells /kg body weight as a single infusion. Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions: mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR). Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide. | Biological: DCreg:2.5 to 5.0 million cells/kg+SOC<br>* DCreg 2.5 to 5.0 million cells/kilogram body weight infused as a single dose. Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions: mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR). Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.<br>* Other names: Regulatory Donor-Derived Dendritic Cells (DCreg);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Outcome: Proportion of Participants who Experience any of the Pre-Specified Safety Events | Safety will be assessed by summarizing the proportion of participants who experience any of the following events from the initiation of the regulatory dendritic cells (DCreg) infusion administered 7 days prior to kidney transplant to 1 year post-transplant: Recipient death attributed to receipt of DCreg, NCI-CTCAE Grade 4 or higher DCreg infusion reaction, NCI-CTCAE Grade 4 or higher infection, Malignancy other than non-melanoma skin cancer, Pre-transplant Donor Specific Antibodies (DSA), Post-transplant DSA, Biopsy-proven acute rejection (BPAR) by BANFF 2017 criteria (grade ≥2A), or Non-surgical graft loss. Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). | Seven Days Prior to Transplant Surgery(e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Death Attributed to Participant Receipt of Regulatory Dendritic Cells (DCreg) | The occurrence of death among participants who receive DCreg treatment. | Seven Days Prior to Transplant Surgery (e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant | 
| Incidence of Adverse Event: CTCAE Grade 4 or Higher Infusion Reaction | The number of Grade 4 or higher infusion reaction(s) among participants who receive regulatory dendritic cells (DCreg) infusion, graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). | Seven Days Prior to Transplant Surgery (e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant | 
| Incidence of Adverse Event:CTCAE Grade 4 or Higher Infection | The number of Grade 4 or higher infection(s) among participants who receive regulatory dendritic cells (DCreg) infusion, graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). | Seven Days Prior to Transplant Surgery (e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant | 
| Incidence of Adverse Event: Malignancy | The number of malignancies among participants who receive regulatory dendritic cells (DCreg) infusion. Not included in this incidence outcome: non-melanoma skin cancer(s). | Seven Days Prior to Transplant Surgery(e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant | 
| Incidence of Pre-Transplant Donor Specific Antibodies (DSA) | The number of pre-transplant DSA among participants occurring after DCreg infusion and before transplant. | Baseline (Seven Days Prior to Transplant Surgery, Pre -Regulatory Dendritic Cells (DCreg)) Infusion) up to within 48 Hours of Transplant | 
| Incidence of Post-Transplant Donor Specific Antibodies (DSA) | A de novo DSA occurring within the first year post-transplant. | Day 0 (Transplant Surgery) up to 1-Year Post-Transplant | 
| Incidence of Biopsy-Proven Acute Rejection | Acute kidney allograft rejection is defined by a kidney (renal) allograft biopsy classification of grade 2A or higher. Classification method: Banff 2013. The Banff 2013 classification for antibody-mediated rejection is a recognized standard in renal allograft pathology. | Day 0 (Transplant Surgery) up to 1-Year Post-Transplant | 
| Incidence of Non-Surgical Graft Loss | Graft loss not associated with the transplant surgery. | Day 0 (Transplant Surgery) up to 1-Year Post-Transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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donor recipient pairs, allogeneic regulatory dendritic cell therapy (DCreg), DCreg therapy, de novo (first) live-donor renal transplant recipients