DCreg Cell Therapy for Kidney Transplant Recipients

(RTB-006 Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Angus W. Thomson PhD DSc

Must not be taking: Immunosuppressants, Investigational drugs

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines a new treatment to make kidney transplants safer and more effective. Researchers aim to determine if regulatory dendritic cells (DCreg), a special type of immune cell, can help prevent the body from rejecting a new kidney from a living donor. The trial tests different doses of DCreg alongside the usual medications given to transplant patients. Individuals planning to receive a kidney from a living donor might be suitable candidates if they have a stable health condition and meet certain health criteria. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require treatment with an immunosuppressive agent, except for a low dose of corticosteroids, or if you have used investigational drugs within 12 weeks before the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that regulatory dendritic cells (DCreg) are being studied for safety in organ transplants. In these studies, patients have received DCreg to determine if it aids in organ acceptance, such as kidneys. The results appear promising.

In some trials, recipients of DCreg did not experience major safety issues. These cells aim to help the immune system accept the new organ without attacking it. No serious side effects have been directly linked to DCreg infusions in these studies. Most participants tolerated the treatments well, experiencing only mild side effects, if any.

As this is an early-stage trial, the primary goal is to ensure DCreg's safety for participants. Researchers are closely monitoring for any issues. The fact that DCreg is already being tested in humans indicates a positive safety profile so far. However, as with any new treatment, some level of risk remains, and participants will be monitored closely throughout the study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for kidney transplant recipients, which relies heavily on immunosuppressive drugs like tacrolimus, prednisone, and mycophenolic acid, DCreg cell therapy introduces a unique approach by using regulatory dendritic cells. These cells are designed to modulate the immune response, potentially reducing the need for high doses of immunosuppressive drugs and their associated side effects. Researchers are excited because this therapy could lead to more precise immune regulation, minimizing organ rejection while preserving kidney function. The distinct dosages of DCreg, from 0.5 to 5.0 million cells/kg, offer a tailored approach that might enhance therapeutic outcomes for transplant patients.

What evidence suggests that this trial's treatments could be effective for kidney transplant recipients?

This trial will evaluate the use of regulatory dendritic cells (DCreg) in kidney transplant recipients. Studies have shown that DCreg cells can help the body accept a new kidney by potentially reducing the immune system's chance of attacking the transplanted organ. Participants in this trial will receive different dosages of donor-derived DCreg cells to assess their effect on altering specific immune cells in the recipient before the transplant. These changes could help lower the risk of rejection. Early findings from animal studies and initial human data suggest that DCreg therapy may be a promising way to improve transplant success. ^{1 3 5 6 7}

Who Is on the Research Team?

Amit D. Tevar, MD, FACS

Principal Investigator

University of Pittsburgh: Starzl Transplantation Institute

Are You a Good Fit for This Trial?

This trial is for first-time kidney transplant recipients from living donors. Participants must understand and consent to the study, have no history of transplants or aggressive kidney disease, be negative for HIV, hepatitis B/C, tuberculosis (or treated if previously positive), and agree to use effective contraception if applicable. Donors must meet standard criteria for kidney donation.

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; 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; 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.

Exclusion Criteria

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and DCreg Infusion

Donor-derived regulatory dendritic cells (DCreg) are prepared from monocytes obtained by leukapheresis and infused into recipients 7 days before renal transplantation

1 week

1 visit (in-person)

Transplant and Immediate Post-Transplant Care

Recipients undergo renal transplantation and receive combination immunosuppressive therapy

1 week

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring for adverse events and graft function

2 years

What Are the Treatments Tested in This Trial?

Interventions

• DCreg

Trial Overview The study tests a single infusion of donor-derived regulatory dendritic cells (DCreg) given to recipients 7 days before their kidney transplant. The goal is to assess safety and feasibility over two years with three different doses of DCreg plus standard care.

How Is the Trial Designed?

Group I: DCreg:2.5 to 5.0 million cells/kg+SOC Experimental Treatment 1 Intervention

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.

Group II: DCreg: 1.2 million cells/kg+SOC Experimental Treatment 1 Intervention

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.

Group III: DCreg: 0.5 million cells/kg+SOC Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Angus W. Thomson PhD DSc

Lead Sponsor

Trials

2

Recruited

40+

University of Pittsburgh

Collaborator

Trials

1,820

Recruited

16,360,000+

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

Current immunosuppressive regimens for organ transplants have significant side effects, including increased risk of infections and cancers, highlighting the need for safer alternatives.

Regulatory dendritic cell therapy shows promise in promoting transplant tolerance and may allow for the reduction or complete withdrawal of immunosuppressive drugs, with early clinical trials currently assessing its efficacy in organ transplantation and autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory dendritic cells for human organ transplantation. Thomson, AW., Metes, DM., Ezzelarab, MB., et al.[2020]

Regulatory dendritic cells (DCregs) have been shown to significantly enhance long-term survival of organ transplants by modulating T-cell responses, based on extensive research in murine models and recent studies in nonhuman primates.

Therapeutic efficacy of DCregs can be achieved through both donor and recipient sources, with promising protocols for their generation and in-situ targeting, paving the way for potential clinical applications in human organ transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orchestration of transplantation tolerance by regulatory dendritic cell therapy or in-situ targeting of dendritic cells. Morelli, AE., Thomson, AW.[2021]

Infusing regulatory dendritic cells (DCreg) in a rhesus macaque model significantly improved renal allograft survival, with median graft survival time increasing from 39.5 days in control monkeys to 113.5 days in DCreg-treated monkeys (p < 0.05).

The DCreg infusion was safe, with no adverse events reported and no signs of host sensitization, indicating a promising therapeutic approach for enhancing organ transplantation outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory dendritic cell infusion prolongs kidney allograft survival in nonhuman primates. Ezzelarab, MB., Zahorchak, AF., Lu, L., et al.[2023]

Regulatory dendritic cells (DCreg) can be generated in vitro and have the potential to reduce inflammation and improve outcomes in organ transplantation by promoting donor-specific immune tolerance.

A proposed phase I/II safety study will investigate the effects of donor-derived DCreg combined with standard immunosuppressive therapy on transplant rejection and immune responses in humans, building on successful results seen in animal models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Clinical Testing of Regulatory Dendritic Cells in Organ Transplantation. Thomson, AW., Zahorchak, AF., Ezzelarab, MB., et al.[2018]

Recent research shows that regulatory dendritic cells (DCreg) have a unique transcriptional program that enhances their ability to promote immune tolerance, which is crucial for organ transplantation.

Innovative methods, including the use of nanovesicles and ex-vivo modifications, are being developed to enhance the function of DCreg, with initial clinical trials underway for their use in living donor kidney and liver transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory dendritic cells: profiling, targeting, and therapeutic application. Thomson, AW., Ezzelarab, MB.[2020]

Regulatory dendritic cells (DCregs) were successfully manufactured in large quantities under Good Manufacturing Practice conditions, achieving a high viability rate of 94% and meeting quality criteria for infusion into 28 liver transplant recipients.

The process resulted in a conversion rate of 28% from monocytes to DCregs, with 92.6% of the products achieving the target cell range for infusion, indicating a promising approach to enhance antigen-specific tolerance in organ transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Manufacturing and validation of Good Manufacturing Practice-compliant regulatory dendritic cells for infusion into organ transplant recipients. Zahorchak, AF., DeRiggi, ML., Muzzio, JL., et al.[2023]

Regulatory dendritic cells (DCregs) show promise as a novel cellular therapy for organ transplantation, with early-phase clinical trials indicating their feasibility and safety in kidney and liver transplants.

Preliminary results suggest that DCregs can reduce effector CD8+ T-cells and influence host immune responses, potentially leading to less reliance on traditional immunosuppressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory dendritic cell therapy in organ transplantation. Hadjiyannis, Y., Thomson, AW.[2023]

Dendritic cells (DCs) play a crucial role in organ transplantation by balancing rejection and tolerance, and regulatory DCs (DCregs) show promise in promoting long-lasting organ-specific tolerance with fewer side effects compared to traditional immunosuppressive treatments.

Early-phase studies on DCreg therapy in living-donor kidney and liver transplants indicate potential safety and efficacy in inducing allograft tolerance, suggesting a new direction for improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance. Que, W., Guo, WZ., Li, XK.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6599577/

Regulatory dendritic cells for human organ transplantation The mainstay of IS therapy in kidney transplantation is use of CNIs. Whereas these drugs have reduced acute rejection rates, they have failed to improve long- ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10932828/

Regulatory Dendritic Cell therapy in Organ Transplantation ** This study reports the first phase I clinical trial, 3-year follow-up data, using human autologous tolerogenic dendritic cells in kidney transplantation and ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1600613522086269

Donor-derived regulatory dendritic cell infusion results in ... Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03726307?term=AREA%5BBasicSearch%5D(dendritic%20cell)&rank=10

Allogeneic Regulatory Dendritic Cell (DCreg) Renal Study This study will evaluate the safety and feasibility of treatment involving a single infusion of donor-derived regulatory dendritic cells (DCreg) in first ...

5. science.org science.org/doi/10.1126/scitranslmed.adf4287

Donor-derived regulatory dendritic cell infusion modulates ... Previously (32), we reported that donor-derived DCreg infusion resulted in peripheral T cell subset changes before transplant.

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0085253822008456

A Phase I/IIa study of autologous tolerogenic dendritic cells ... We present the first phase I clinical trial results using human autologous tolerogenic dendritic cells (ATDC) in kidney transplantation.

7. kidney-international.org kidney-international.org/article/S0085-2538(22)00845-6/abstract

A Phase I/IIa study of autologous tolerogenic dendritic cells ... Here, we present the first phase I clinical trial results using human autologous tolerogenic dendritic cells (ATDC) in kidney transplantation.