DCreg Cell Therapy for Liver Transplant Recipients

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Angus W. Thomson PhD DSc

Must be taking: Immunosuppressants

Disqualifiers: Severe heart or lung disease, others

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

Compensation: Varies

Number of Visits: 1

24 Participants Needed

Trial Summary

What is the purpose of this trial?

Phase I/II, single center, prospective, open-label, non-controlled, non-randomized, interventional, cohort study in which low risk living donor liver transplant (LDLT) recipients who are between 1 and 3 years after transplantation and meet specific criteria (no positive crossmatch, no clinically treated rejection within 2 years preceding enrollment, permissive liver function tests (LFTs) within 30 days preceding enrollment, no prior liver biopsy showing significant fibrosis or ductopenia\*) will be enrolled and will undergo a protocol liver biopsy unless they have had a permissive liver biopsy\*\* within 90 days of anticipated immunosuppression weaning. Those patients with permissive liver biopsy\*\* will then receive a single infusion of donor-derived DCreg and will remain on their current standard of care (SOC) immunosuppression. One week after DCreg infusion, immunosuppression weaning will be initiated. Recipients will be slowly weaned off immunosuppression. Successfully weaned participants who remain rejection-free will undergo 3 years of follow-up after the last dose of immunosuppression. They will undergo a liver biopsy at 1 yr and 3 yrs after immunosuppression withdrawal. Participants who are removed from the study protocol at any time will return to standard of care but will continue to be followed by the study team and will undergo a liver biopsy at the end of the study. \* Permissive LFTs are defined as ALT, AST and total bilirubin \< 2.5 times the upper limit of normal. \*\*A permissive biopsy is based on 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology (the criteria detailed in Table 8, Demetris et al. 2016).

Do I have to stop taking my current medications for the trial?

Participants will remain on their current standard immunosuppression medications initially, but will begin to slowly reduce these medications one week after receiving the DCreg infusion.

What data supports the effectiveness of the treatment Donor-derived DCreg for liver transplant recipients?

Research shows that donor-derived regulatory dendritic cells (DCreg) can help liver transplant patients by reducing immune responses that could lead to organ rejection. In studies, patients who received DCreg had fewer immune cells that attack the transplanted liver and showed changes in immune cell behavior that may allow for reduced use of other immune-suppressing drugs. ^{1 2 3 4 5}

Is DCreg cell therapy safe for liver transplant recipients?

Early-phase clinical trials suggest that DCreg cell therapy is generally safe for liver transplant recipients, with no infusion reactions reported in a study involving 15 patients. This therapy aims to reduce the need for traditional immunosuppressive drugs, which can have serious side effects. ^{1 2 6 7 8}

How does DCreg cell therapy differ from other treatments for liver transplant recipients?

DCreg cell therapy is unique because it uses regulatory dendritic cells to promote transplant tolerance, potentially reducing the need for traditional immunosuppressive drugs that can have serious side effects. This therapy involves a single infusion of donor-derived cells before transplantation, which modulates immune responses and may help in reducing the risk of organ rejection. ^{1 2 3 6 9}

Research Team

Abhinav Humar

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for low-risk liver transplant recipients who are 1-3 years post-transplant without recent rejection or significant fibrosis. They must have stable liver function and no severe other diseases. Donors must be healthy, able to consent, and free from certain infections like HIV or hepatitis.

Inclusion Criteria

Negative for HIV (5th generation Test and NAT), HTLV-1, HTLV-2;(a)

I haven't received any live vaccines in the last 12 weeks.

Negative for hepatitis C (antibody and NAT), hepatitis B (surface antigen and NAT)(a) (does not preclude donors from undergoing leukapheresis but cells may not be infused into recipient)

Exclusion Criteria

I have or had Hepatitis B or C, but it's not currently active.

Prior other solid organ transplant

Positive antigen-antibody immunoassay for HIV-1/2

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

DCreg Infusion

Participants receive a single infusion of donor-derived regulatory dendritic cells (DCreg) one week prior to the initiation of immunosuppression weaning

1 week

1 visit (in-person)

Immunosuppression Weaning

Participants are slowly weaned off immunosuppression following the DCreg infusion

Varies per participant

Follow-up

Participants are monitored for safety and effectiveness after immunosuppression withdrawal, including liver biopsies at 1 year and 3 years post-withdrawal

3 years

Regular visits (in-person)

Treatment Details

Interventions

• Donor-derived DCreg

Trial Overview The study tests a single infusion of donor-derived DCreg cells in patients after living donor liver transplantation. It aims to see if these cells can allow safe reduction of immunosuppression drugs over time with follow-up biopsies at one and three years post-weaning.

Participant Groups

Group I: DCreg Prior to Weaning Experimental Treatment 1 Intervention

Regulatory dendritic cells that were derived from the recipient's liver donor will be infused into the recipient one week prior to the initiation of immunosuppression weaning.

Who Is Running the Clinical Trial?

Angus W. Thomson PhD DSc

Lead Sponsor

Trials

2

Recruited

40+

Findings from Research

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Manufacturing and validation of Good Manufacturing Practice-compliant regulatory dendritic cells for infusion into organ transplant recipients. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Donor-derived regulatory dendritic cell infusion modulates effector CD8+ T cell and NK cell responses after liver transplantation. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Effects of liver-derived dendritic cell progenitors on Th1- and Th2-like cytokine responses in vitro and in vivo. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Regulatory dendritic cell therapy in organ transplantation. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Regulatory dendritic cells for human organ transplantation. [2020]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Prospective Clinical Testing of Regulatory Dendritic Cells in Organ Transplantation. [2018]