Immunological Tolerance Therapy for Kidney Transplant Rejection

Overseen By Dana Levin-Lopez, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, Los Angeles

Must not be taking: Immunosuppressants, Immunotherapy

Disqualifiers: Previous transplant, Active infection, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the drug belumosudil can safely help kidney transplant recipients more easily accept their new organ. It targets individuals receiving a kidney and stem cell transplant from a partially matched donor. Eligible participants may have a living donor, are undergoing both kidney and stem cell transplants, and reside within a few hours of UCLA for the first six months post-transplant. The trial is experimental, seeking to improve transplant success by reducing the need for strong immune-suppressing drugs. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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

The trial requires that you have not taken immunosuppressive medications within one year of the study treatment, except for short-term corticosteroids that were stopped at least 4 weeks before the kidney transplant. Other specific medication restrictions are not mentioned, so it's best to discuss your current medications with the study team.

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

In previous studies, researchers tested belumosudil (Rezurock) for safety. Research shows it is generally well-tolerated. Common side effects include tiredness, diarrhea, and nausea, but these are usually mild. Serious side effects occur less frequently. Notably, belumosudil is already approved for treating another condition, suggesting a degree of safety.

For donor CD34+ and CD3+ cells, studies show that using these cells in kidney transplants aims to help the body accept the new kidney. While detailed safety information for this specific use isn't available, clinical testing has occurred. This method often involves closely monitoring the patient to manage any possible side effects.

Overall, both treatments have been studied in various settings, focusing on safety and improving transplant outcomes. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for kidney transplant rejection because it aims to establish immune tolerance, potentially eliminating the need for lifelong immunosuppressive drugs. Unlike standard treatments that rely heavily on continuous immunosuppressive medication, this approach combines hematopoietic stem cell transplantation with a kidney transplant, aiming to train the recipient's immune system to accept the new organ as its own. The use of Belumosudil, along with donor-derived CD34+ and CD3+ cells, represents a novel method to encourage this immune tolerance. This could significantly reduce the risks of rejection and other complications associated with traditional immunosuppression.

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

In this trial, participants will receive a combination of treatments to promote immune tolerance in mismatched kidney transplant recipients. Research has shown that belumosudil, a pill included in this trial, can block certain proteins involved in the immune system. It is already approved to treat chronic graft-versus-host disease (cGVHD), a serious condition where donated cells attack the patient's body, suggesting it might help control immune responses in kidney transplant patients. Belumosudil could potentially help the body accept the new kidney, making it a promising option for reducing rejection.

Additionally, this trial involves the use of donor CD34+ stem cells. Past studies have shown that patients who received these stem cells maintained stable kidney function for years, suggesting they might help the body accept the new kidney better. These findings offer hope for improved transplant outcomes with these treatments. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

Adults over 18 eligible for kidney and stem cell transplants can join this trial if they have a matched living donor, are not pregnant, agree to use contraception, live near UCLA Medical Center, and have good heart, liver, and lung function. Excluded are those with certain infections or diseases requiring immunosuppression, recent drug abuse history, very high BMI or previous organ transplants.

Inclusion Criteria

Adequate social support based on evaluation by the UCLA renal transplant team licensed clinical social worker

INR and/or PTT < 1.5X upper limits of institutional normal

Resides or is willing to stay within 3 hours distance from University of California, Los Angeles Medical Center by ground transportation for the first six months post-kidney transplant

Exclusion Criteria

I have been treated with rATG or am allergic to rabbit proteins.

Pregnant or lactating

INR and/or PTT ≥ 1.5X upper limits of institutional normal

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Subjects undergo a conditioning regimen of rATG and TLI followed by kidney transplantation and infusion of donor CD34 and CD3 cells.

Immediate post-transplant

In-patient stay for transplantation and initial treatment

Treatment

Participants receive a triple immunosuppressive regimen and belumosudil. Corticosteroids taper from day 0 to month 4, tacrolimus taper from day 1 to month 18, and mycophenolate from day 11 to month 12. Belumosudil is administered from day 28 to month 24.

24 months

Regular follow-up visits for monitoring and biopsies

Follow-up

Participants are monitored for safety and effectiveness after treatment, including chimerism measurement, graft function monitoring, and protocol biopsies.

36 months

What Are the Treatments Tested in This Trial?

Interventions

• Belumosudil
• Donor CD34+, CD3+

Trial Overview

The study is testing the safety and effectiveness of belumosudil in improving transplant tolerance when given alongside a combined kidney and hematopoietic stem cell transplant from either a half-matched related donor or an unrelated donor with minimal HLA mismatches.

How Is the Trial Designed?

Group I: Immune tolerance in mismatched kidney transplant recipient Experimental Treatment 1 Intervention

Our goal is to establish this regimen as a novel, safe and effective approach for induction of transplant tolerance in HLA single haplotype-matched related and HLA mismatched unrelated recipients of combined Hematopoietic Stem Cell Transplant(HSCT)/ Kidney Transplant (KT). Patients will undergo conditioning with rATG and TLI, followed by infusion of hematopoeitic stem cells from the same donor, a triple immunosuppressive regimen, and receive belumosudil following the kidney transplant. Immunosuppression taper will be stopped and/or immunosuppression will be resumed for any of the following conditions: (1) loss of chimerism 2) clinical or pathological evidence of acute rejection and (3) clinical or pathological evidence of graft vs host disease.

Belumosudil is already approved in United States, Canada for the following indications:

Approved in United States as Rezurock for:

• Chronic graft-versus-host disease (cGVHD) in patients aged 12 years and older after failure of at least two prior lines of systemic therapy

Approved in Canada as Rholistiq for:

• Chronic graft-versus-host disease (cGVHD) in adult and pediatric patients 12 years or older

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

Published Research Related to This Trial

Desensitization using carfilzomib and lulizumab in a non-human primate model significantly reduced donor-specific antibodies and improved kidney graft survival, with a median survival time of 64.8 days compared to 5.8 days in control animals.

The treatment shifted the immune system towards a more naive phenotype, maintaining regulatory T cells and increasing naive CD4 T and B cells, although all desensitized subjects eventually developed antibody-mediated rejection (AMR) and graft failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model. Schroder, PM., Schmitz, R., Fitch, ZW., et al.[2022]

A modified release tacrolimus formulation (MR4) is currently in phase III trials and aims to improve kidney transplant outcomes by allowing once-daily administration while maintaining the same therapeutic target levels as the original formulation.

Belatacept (LEA29Y), a second-generation immunosuppressant, has shown comparable efficacy to ciclosporin in phase II trials and is now in phase III trials, indicating its potential as a viable alternative for kidney transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy for De Novo renal transplantation: what's in the pipeline? Tedesco Silva, H., Pinheiro Machado, P., Rosso Felipe, C., et al.[2018]

In a study of 316 kidney transplant recipients over 2 years, belatacept-based immunosuppression showed a significantly lower incidence of reduced kidney function (eGFR <45 ml/min) compared to tacrolimus, indicating better long-term kidney health.

However, belatacept was associated with a higher rate of biopsy-proven acute rejection compared to tacrolimus, suggesting a trade-off between reduced nephrotoxicity and increased rejection risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial. Kaufman, DB., Woodle, ES., Shields, AR., et al.[2023]

Citations

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Immunological Tolerance Therapy for Kidney Transplant ...

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Belumosudil (KD025) | ROCK2 Inhibitor

End Stage Kidney Disease|Immunological Tolerance|Kidney Transplant Failure and Rejection|Chronic Kidney Diseases ... SAFETY DATA SHEET (SDS). English - EN ...