Stem Cell Infusion for Immune Tolerance in Liver Transplant

(iTILT Trial)

Overseen By Cray V. Noah, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Jeffrey Veale, MD

Must not be taking: Immunotherapy drugs, Hepatotoxic drugs

Disqualifiers: Active infection, HIV, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 13

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to help people who have had a liver transplant stop taking long-term immunosuppressive drugs, which can cause serious side effects. Researchers use donor hematopoietic stem and progenitor cell infusion (a type of stem cell treatment) to train the immune system to accept the new liver as part of the body. Participants who might be a good fit have received a living-donor liver transplant from the same donor, and the transplant must be at least a year old and functioning well. 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.

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop your current medications, but it aims to help participants eventually stop taking immunosuppressive drugs. If you are on medications with known liver toxicity, they must be reviewed and approved by the study's Principal Investigator, and your liver function tests should be stable for at least 6 months.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that donor stem cells are being tested to help liver transplant patients reduce or stop taking immune-suppressing drugs. Although these drugs are necessary, they can cause serious side effects. Studies have found that patients who received stem cell infusions had fewer circulating stem cells after the transplant, which then moved to the liver without causing immediate harm.

Additionally, patients who underwent similar treatments for other conditions generally tolerated the procedure well, with serious side effects being uncommon. However, since this trial remains in its early stages, more information is needed to fully understand the treatment's safety. If proven safe, this treatment could allow liver transplant patients to live without lifelong medication. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike standard treatments for liver transplant patients, which typically involve long-term immunosuppressive drugs to prevent rejection, this stem cell infusion approach aims to induce immune tolerance. Researchers are excited because this method uses donor hematopoietic stem and progenitor cells to potentially enable the recipient's immune system to accept the liver without ongoing medication. By conditioning the body with total lymphoid irradiation and rabbit anti-thymocyte globulin, followed by the stem cell infusion, there's hope for achieving donor chimerism, which may allow patients to taper off immunosuppressants entirely if successful. This could significantly reduce the side effects and risks associated with lifelong immunosuppression.

What evidence suggests that donor stem cell infusion is effective for immune tolerance in liver transplant recipients?

Research has shown that using donor stem cells, as studied in this trial, can help liver transplant patients reduce or even stop taking immunosuppressive drugs. Participants in the Tolerance Induction Arm will receive donor hematopoietic stem and progenitor cell infusions. These cells can train the immune system to accept the new liver as part of the body, a process known as "immune tolerance." Studies have found that this method can create a mix of donor and recipient cells without causing serious side effects like graft-versus-host disease (GVHD). Patients who reach this state can often safely reduce or stop their medication, avoiding the harmful side effects of long-term drug use. This approach has succeeded with kidney transplant patients, suggesting it could also benefit liver transplant recipients. ^{1 5 6 7 8}

Who Is on the Research Team?

Jeffrey Veale, MD

Principal Investigator

UCLA Health

Cray V. Noah, MD

Principal Investigator

UCLA Health

Are You a Good Fit for This Trial?

This trial is for liver transplant recipients who are interested in potentially stopping their immunosuppressive medications, which are usually required for life. Specific eligibility criteria details were not provided.

Inclusion Criteria

1. Males and females ages 18 years and older with a pre-existing liver transplant from a living donor with a donor-recipient match at 6 or more out of 12 alleles across the HLA-A, -B, -C, -DR, -DQ, and -DP loci, as determined by high-resolution HLA typing.

2. Pre-existing living-donor liver transplant must be 12 months to 20 years from date of scheduled HSPC infusion.

3. Agreement to participate in the study and ability to give informed consent.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo a conditioning regimen with total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (rATG) over two weeks

2 weeks

Outpatient visits for TLI and rATG administration

HSPC Infusion

Infusion of mobilized donor hematopoietic stem and progenitor cells (HSPC) on the final day of conditioning

1 day

1 visit (in-person)

Immunosuppression Taper

Structured taper of maintenance immunosuppression with the goal of complete withdrawal if donor chimerism is present and protocol criteria are met

6-12 months

Regular monitoring visits

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes such as graft function, chimerism, and quality of life

48 months

Regular follow-up visits at 12, 24, 36, and 48 months

What Are the Treatments Tested in This Trial?

Interventions

• Donor Hematopoietic Stem and Progenitor Cell Infusion

Trial Overview The study tests a 'Delayed Tolerance' approach where after a conditioning regimen, patients receive donor stem cell infusions to teach their immune system to recognize the transplanted liver as its own and prevent rejection without long-term drugs.

How Is the Trial Designed?

Group I: Tolerance Induction Arm Experimental Treatment 1 Intervention

Adult recipients with a pre-existing, well-functioning HLA-matched living-donor liver transplant from the same donor will undergo outpatient conditioning with total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (rATG), followed by infusion of mobilized donor hematopoietic stem and progenitor cells (separate CD34+ and CD3+ fractions). After HSPC infusion, participants will be monitored for donor chimerism, graft function, rejection, and GVHD, and will undergo a structured taper of maintenance immunosuppression with the goal of complete withdrawal if donor chimerism is present and protocol criteria are met.

Who Is Running the Clinical Trial?

Jeffrey Veale, MD

Lead Sponsor

Trials

1

Recruited

20+

University of California, Los Angeles

Collaborator

Trials

1,594

Recruited

10,430,000+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7461870/

Immune Tolerance Induction Using Cell-Based Strategies ... Cell-based strategies are one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT07269041

Immune Tolerance Induction After Liver Transplantation ... This study seeks to determine if patients with a pre-existing, well-functioning liver transplant from an HLA-matched living donor can be ...

3. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01326/pdf

Progress in Liver Transplant Tolerance and ... This article will review the current status of liver transplant tolerance and the research progress of different cellular immunotherapies to ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1665268122001028

Immunotolerance in liver transplantation: a primer for the ... Donor NK cells are thought to be promoters of immune tolerance (either by mounting a direct anti-inflammatory response or by lysing recipient inflammatory cells) ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11288126/

Donor and recipient hematopoietic stem and progenitor cells ... Donor HSPCs chimerism was found at negligible levels in recipient blood without GVHD after LTx. Donor HSPCs is believed to be involved in post-transplant immune ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39075608/

Donor and recipient hematopoietic stem and progenitor ... Recipients exhibited a decline in blood-circulating HSPCs after transplant, the cells mobilized into the blood and migrated to target tissue ...

7. journals.lww.com journals.lww.com/ajg/fulltext/2008/09001/safety_and_efficacy_of_hepatic_progenitor_cell.355.aspx

Safety and Efficacy of Hepatic Progenitor Cell... Purpose: Orthotopic liver transplantation (OLT) is the ultimate treatment for end-stage liver failure and for numerous liver based inborn errors of metabolism.

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1001929414600183

Clinical Outcome of Autologous Hematopoietic Stem Cell ... To investigate the efficacy of hematopoietic stem cell (HSC) transplantation via the hepatic artery vs. the portal vein for end-stage liver disease (ESLD).