Cellular Therapy for Liver Transplant Recipients

(LITTMUS-MGH Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Glucocorticoids, Immunosuppressives

Disqualifiers: HIV, Autoimmune liver disease, others

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

Compensation: Varies

Number of Visits: 53

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cellular therapy called arTreg-CSB to help liver transplant recipients reduce their need for ongoing immunosuppression (medications that prevent organ rejection). The goal is to determine if this therapy can enable patients to safely lower or stop these medications after a liver transplant. Participants with end-stage liver disease on the waiting list for a liver transplant, either from living or deceased donors, might be suitable candidates. This includes those who test positive for Epstein-Barr virus (a common viral infection) antibodies. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from 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, if you are on chronic immunosuppressive drugs or systemic glucocorticoids, you may not be eligible to participate.

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

Research has shown that arTreg-CSB therapy has been evaluated for safety and tolerability. In previous studies, patients generally managed the treatment well without serious problems. Specifically, no major side effects prevented dose escalation. The treatment uses special cells called Tregs, a type of immune cell, to help the body accept a liver transplant with less need for immunosuppressive medication.

Supportive treatments, such as everolimus (a drug that helps prevent organ rejection), have been used in other medical situations and are generally well-tolerated. Overall, early findings suggest that combining arTreg-CSB with these treatments is safe. However, discussing any concerns with a healthcare provider is always important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike traditional immunosuppressive drugs used in liver transplant patients, which often suppress the entire immune system, arTreg-CSB specifically uses donor alloantigen-reactive T regulatory cells. This targeted approach aims to promote immune tolerance specifically towards the transplanted liver, potentially reducing the risk of rejection with fewer side effects. Researchers are excited about arTreg-CSB because it offers a novel way to precisely modulate the immune response, which could lead to better long-term outcomes and improved quality of life for transplant recipients.

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

Research has shown that treatments like arTreg-CSB, which participants in this trial will receive, could benefit individuals who have had liver transplants. These treatments are generally safe and might help the body accept the new liver, reducing the need for long-term use of immunosuppressive drugs. Early studies suggest that regulatory T cells, a type of immune cell, can help the body tolerate the new liver. Using donor-specific regulatory T cells may specifically target and reduce unwanted immune reactions against the new liver. Although more research is needed, these early results are promising for liver transplant patients considering this treatment. ^{1 2 3 6 7}

Who Is on the Research Team?

James F. Markmann, MD, PhD

Principal Investigator

University of Pennsylvania Medical Center: Transplantation

Are You a Good Fit for This Trial?

This trial is for liver transplant recipients with a positive Epstein-Barr virus test, who've completed treatment for HCV if applicable. Living donors must meet specific eligibility and manufacturing requirements. Contraception use is required, and vaccinations should be up to date. Exclusions include contraindications to certain drugs, chronic conditions that can't pause anticoagulation or immunosuppression, significant heart disease not cleared by a cardiologist, high-risk malignancies, and any factors affecting study compliance.

Inclusion Criteria

I understand the study and can give my consent.

Recipient:

Agreement to use contraception

Exclusion Criteria

I am allergic or react badly to cyclophosphamide or Mesna.

I don't have CMV antibodies, but my donor does.

Factors potentially hampering compliance with the study protocol and follow-up visit schedule

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of Treg product (arTreg-CSB) via IV infusion

1 day

1 visit (in-person)

Immunosuppression Withdrawal

Participants attempt to withdraw from all immunosuppression over 52 weeks

52 weeks

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including research biopsies at 52 and 104 weeks

104 weeks

Research biopsies at 52 and 104 weeks

What Are the Treatments Tested in This Trial?

Interventions

• arTreg-CSB
• Cyclophosphamide
• Everolimus
• Mesna

Trial Overview The trial tests cellular therapy aiming to reduce the need for immunosuppression in liver transplant patients using everolimus (a drug), arTreg-CSB (modified T cells), leukapheresis (a procedure to collect white blood cells), cyclophosphamide and mesna (chemotherapy agents). It's an open-label study at MGH where participants are openly given these interventions without randomization.

How Is the Trial Designed?

Group I: arTreg-CSB Experimental Treatment 5 Interventions

arTreg CSB: alloantigen-reactive T regulatory cells costimulatory blockade per protocol. The investigational product is donor alloantigen-specific T regulatory cells (arTreg-CSB). Supportive regimen for receipt of arTregs-CSB includes everolimus, leukapheresis, cyclophosphamide, and mesna. Participants will receive a single dose of Treg product (arTreg-CSB). The target dose is 2.5 to 125 x 10\^6 total cells. arTreg-CSB will be administered as a single peripheral intravenous (IV) infusion over approximately 15 to 30 minutes. Note: Participants who receive at least the minimum Treg product (arTreg-CSB) dose of 1 to \< 2.5 x 10\^6 cells will be included in intent-to-treat analysis.

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Immune Tolerance Network (ITN)

Collaborator

Trials

68

Recruited

7,900+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11016119/

Selective decrease of donor-reactive Tregs after liver ... Selective decrease of donor-reactive T regs after liver transplantation limits T reg therapy for promoting allograft tolerance in humans.

2. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/19/NCT02188719/Prot_000.pdf

Donor-Alloantigen-Reactive Regulatory T Cell Therapy in ... This is based on data from the de novo liver transplant EVR trial. Participants who had a trough level of 6-8 µg/mL required a mean (median, standard ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2589555925000710

Regulatory T cell therapy in autoimmune liver disease and ... In this review, we explore the application of regulatory T cells (Tregs) as cellular therapies in the setting of autoimmune liver diseases and liver ...

4. withpower.com withpower.com/trial/phase-2-2-2019-e960a

Cellular Therapy for Liver Transplant Recipients Research shows that cellular therapies, including mesenchymal stromal cells and regulatory T cells, have been generally safe for liver transplant patients.

5. mayo.edu mayo.edu/research/clinical-trials/cls-20272688

A Study of Donor-Alloantigen-Reactive Regulatory T Cell ... The purpose of this study is to assess the safety, tolerability, and dose limiting toxicities of taking a specific combination of immunosuppressant drugs on ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03654040

NCT03654040 | Liver Transplantation With Tregs at UCSF The investigational product is donor alloantigen-reactive regulatory T cells (arTreg). Supportive regimen for receipt of arTregs includes everolimus, ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12266500/

Regulatory T cell therapy in autoimmune liver disease and ... In this review, we explore the application of regulatory T cells (Tregs) as cellular therapies in the setting of autoimmune liver diseases and liver ...