Kidney + Stem Cell Transplant for Kidney Transplant Rejection

(OneLegacy Trial)

Overseen By Jenny Lester

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Jeffrey Veale, MD

Must not be taking: Immunosuppressives, Immunotherapy

Disqualifiers: Previous transplant, Active infection, Malignancy, others

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

Compensation: Varies

Number of Visits: 1

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to help kidney transplant recipients accept their new kidney more effectively and eliminate the need for immunosuppressive medicines. The treatment begins after a kidney transplant and includes a combination of a special drug and radiation, followed by a stem cell infusion using donor CD34+ and CD3+ cells from the sibling donor. Researchers are testing whether this approach can prevent rejection and reduce side effects from current medications. The trial suits those who have received a kidney transplant from a sibling and can easily travel to UCLA Medical Center for follow-ups. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

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

The trial protocol does not specify if you must stop all current medications. However, you cannot have taken certain immunosuppressive medications or immunotherapy drugs within six months before the study treatment. Corticosteroids are allowed if they were prescribed for a short period and stopped at least four weeks before the kidney transplant.

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

Research has shown that using certain donor cells in kidney transplants is generally safe. One study found that this method helped maintain stable kidney function over time and reduced the need for medications that weaken the immune system. Another study confirmed the safety of using donor stem cells in kidney transplants, although the full benefits remain not completely understood. These findings are promising and suggest that the treatment is well-tolerated. However, this research is still in the early stages, so more studies are needed to confirm these results. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Most treatments for kidney transplant rejection rely on immunosuppressive drugs to prevent the body's immune system from attacking the new kidney. However, this new treatment is unique because it uses stem cell technology to potentially create a more tolerant immune environment. Researchers are excited about this approach because it involves infusing donor CD34+ and CD3+ cells, which are derived from a living, HLA-identical sibling donor. This method aims to promote immune tolerance and reduce the need for long-term immunosuppressant drugs, which can have significant side effects. By potentially minimizing rejection and drug dependency, this treatment could improve the longevity and quality of life for kidney transplant recipients.

What evidence suggests that this treatment might be an effective treatment for kidney transplant rejection?

In this trial, participants will receive an infusion of donor CD34+ and CD3+ cells. Research has shown that these donor cells can help kidney transplant patients accept their new kidney more easily. In earlier studies, patients who received CD34+ stem cell infusions did not reject the new kidney for several months post-transplant. These stem cells, along with CD3+ cells, aim to harmonize the donor's and recipient's immune systems, a situation known as "mixed chimerism." This approach might enable patients to discontinue the usual drugs needed to prevent organ rejection, which often cause side effects. ^{1 6 7 8 9}

Who Is on the Research Team?

Jeffrey Veale, MD

Principal Investigator

University of California, Los Angeles

Are You a Good Fit for This Trial?

This trial is for adults over 18 who need a kidney transplant and can receive one from their sibling. They must be healthy enough for the procedure, with good heart and lung function, normal blood tests, and no severe infections or recent heavy drug use. Women of childbearing age must not be pregnant and agree to use contraception.

Inclusion Criteria

Resides or is willing to stay within 3 hours distance from UCLA Medical Center by ground transportation for the first three to six months of the trial at the physician's discretion

If female of reproductive potential, must be confirmed not pregnant by a serum or urine pregnancy test and must agree to practice a reliable form of contraception for at least 12 months post-transplant

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

Exclusion Criteria

My donor is my identical twin.

I have received transplants for more than one organ.

I haven't had any cancer except for non-dangerous skin cancer in the last 5 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Transplant and Pre-conditioning

Participants receive a kidney transplant followed by a pre-conditioning regimen of rATG and TLI

2 weeks

Daily visits for rATG and TLI administration

Stem Cell Infusion

Infusion of CD34+ and CD3+ cells from an HLA-identical sibling donor

1 day

1 visit (in-person)

Follow-up

Participants are monitored for graft function, chimerism, and potential rejection

48 months

Regular visits for monitoring and protocol biopsies

What Are the Treatments Tested in This Trial?

Interventions

• Donor CD34+ and CD3+ cells

Trial Overview The study is testing a new treatment that combines drugs (rATG), radiation therapy (TLI), and an infusion of donor stem cells after receiving a kidney from a sibling. The goal is to see if this approach helps patients accept the new organ without needing lifelong immunosuppressive drugs.

How Is the Trial Designed?

Group I: Donor CD34+ and CD3+ cell infusion Experimental Treatment 1 Intervention

The investigational products are (1) an intravenous infusion of granulocyte colony-stimulating factor (GCSF)-mobilized, Miltenyi-enriched CD34+ cells (≥ 5 million cells per kilogram) followed by (2) an infusion of CD3+ cells (5 million cells per kilogram) from an HLA-identical sibling living donor. The cells are infused around Day 11 post-transplant after the following pre-conditioning regimen: 1. 5 doses of rATG (1.5 mg/kg IV per day for 5 days, starting on the day of transplant) 2. 10 doses of TLI (120 centigray \[cGY\] x 10 fractions, starting the day after transplant)

Who Is Running the Clinical Trial?

Jeffrey Veale, MD

Lead Sponsor

Trials

1

Recruited

20+

OneLegacy Foundation

Collaborator

Trials

2

Recruited

60+

Published Research Related to This Trial

Injecting donor-derived CD34+ bone marrow stem cells into kidney transplant recipients can help induce tolerance, which is a key goal in transplantation.

In a clinical trial, the infusion of these cells was found to be safe and well tolerated, with no adverse effects reported, highlighting their potential for improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data. De Pauw, L., Toungouz, M., Goldman, M.[2004]

Facilitating cells play a crucial role in enhancing stem cell engraftment and promoting tolerance in kidney transplant recipients, as they help stem cells survive and migrate effectively through the secretion of various growth factors.

A phase-2 clinical trial using FCRx therapy, which is enriched with stem and facilitating cells, successfully induced tolerance in over 70% of kidney transplant patients, allowing them to withdraw from immunosuppressive drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Facilitating cells: role in inducing transplantation tolerance. Chhabra, AY., Ildstad, ST.[2019]

Recent advancements in achieving hematopoietic chimerism could improve the chances of developing immunological tolerance in kidney transplant recipients.

This approach may lead to better transplant outcomes by reducing the risk of organ rejection, although specific study details and participant numbers are not provided.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The quest for transplantation tolerance: have we finally sipped from the cup? Markmann, JF., Kawai, T.[2021]

In a study of 50 patients with Acute T Cell-Mediated Rejection (ATCMR), the presence of Th17 cells was associated with poorer graft outcomes, suggesting their significant role in influencing the success of kidney transplants.

The ratio of FOXP3 (a marker for regulatory T cells) to Th17 cells was higher in patients with stable graft function, indicating that a balance between these cell types may be important for a positive response to rejection therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The relationship between T-cell infiltration in biopsy proven acute T-cell mediated rejection with allograft function and response to therapy: A retrospective study. Tehrani, HA., Einollahi, B., Ahmadpoor, P., et al.[2022]

In a study examining the interaction between recipient T-cells and donor renal tubular epithelial cells (TECs), it was found that memory CD4 T-cells, particularly those expressing the CD28 marker, significantly proliferate in response to TECs, which may contribute to kidney graft damage despite immunosuppressive treatment.

While common immunosuppressive drugs like tacrolimus and everolimus effectively suppressed overall CD4 T-cell proliferation, they were unable to inhibit the specific proliferation of CD4CD28 memory T-cells, suggesting that these cells could play a critical role in cellular rejection even under full immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Substantial proliferation of human renal tubular epithelial cell-reactive CD4+CD28null memory T cells, which is resistant to tacrolimus and everolimus. Demmers, MW., Baan, CC., Janssen, M., et al.[2017]

Inducing immune tolerance in kidney transplantation can potentially eliminate the need for long-term immunosuppression, which is crucial for improving long-term outcomes and reducing toxicity associated with current treatments.

Clinical protocols using chimerism induction have successfully achieved immune tolerance in a significant number of HLA-mismatched donor-recipient pairs, although differences in tolerance mechanisms between animal models and humans highlight the need for further research to optimize these approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimerism-Based Tolerance to Kidney Allografts in Humans: Novel Insights and Future Perspectives. Podestà, MA., Sykes, M.[2022]

This study reports the successful induction of immunological tolerance in three patients who received a kidney and hematopoietic stem cell transplant from HLA-identical siblings, with all patients remaining off immunosuppression for up to 4 years without rejection or graft-versus-host disease.

The approach demonstrated not only the feasibility of achieving tolerance but also maintained the patients' immune responses, as evidenced by their strong reactions to the mRNA COVID-19 vaccine, indicating a preserved ability to respond to infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Induction of Specific Immunological Tolerance by Combined Kidney and Hematopoietic Stem Cell Transplantation in HLA-Identical Siblings. Fehr, T., Hübel, K., de Rougemont, O., et al.[2022]

In a study involving seven patients with multiple myeloma and end-stage renal disease, combined kidney and bone marrow transplantation led to sustained renal function and tolerance without ongoing immunosuppression in three patients, demonstrating the potential for long-term success.

All patients achieved mixed chimerism, and five are alive with four showing no signs of myeloma up to 12.1 years post-transplant, indicating that this approach can effectively manage both renal and cancer conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of recipients of combined human leukocyte antigen-matched bone marrow and kidney transplantation for multiple myeloma with end-stage renal disease. Spitzer, TR., Sykes, M., Tolkoff-Rubin, N., et al.[2022]

In a study of 52 adult patients undergoing T-cell-replete HLA-mismatched allogeneic hematopoietic stem cell transplantation, a higher graft CD3+ T-cell dose was linked to a significantly lower risk of relapse (14.3% vs. 67.5%) and improved relapse-free survival (94% vs. 83%) over two years.

Despite the benefits in reducing relapse rates, the study found no significant difference in the incidence of acute or chronic graft-versus-host disease (GvHD) between low and high CD3+ T-cell dose groups, indicating that higher T-cell doses may enhance efficacy without increasing GvHD risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Impact of Graft CD3+ T-Cell Dose on the Outcome of T-Cell Replete Human Leukocyte Antigen-Mismatched Allogeneic Hematopoietic Peripheral Blood Stem Cells Transplantation. Halahleh, K., Mustafa, R., Sarhan, D., et al.[2023]

In a study of 61 kidney transplant patients, those who received donor-specific bone marrow cell infusions showed a significantly higher rate of chimerism (87.5%) compared to those who did not receive the infusion (40.5%), indicating enhanced integration of donor cells.

Patients with detectable chimerism experienced a lower rate of acute rejection (19.4%) compared to those without chimerism (44%), suggesting that donor-specific bone marrow cell infusion promotes immune tolerance and reduces the risk of organ rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of donor-specific bone marrow cell infusion on chimerism and acute rejection in kidney transplantation]. Fu, YW., Wang, WG., Zhou, HL., et al.[2006]

In a study of 159 kidney transplant patients, using autologous mesenchymal stem cells (MSCs) instead of traditional antibody induction therapy led to a significantly lower incidence of acute rejection (7.5% and 7.7% in MSC groups vs. 21.6% in the control group).

Patients receiving MSC treatment also experienced faster recovery of renal function, with improved eGFR levels, and a reduced risk of opportunistic infections compared to those receiving standard anti-IL-2 receptor antibody therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. Tan, J., Wu, W., Xu, X., et al.[2022]

In a phase II clinical trial involving 52 patients with chronic kidney disease (CKD), the infusion of autologous CD34+ cells was found to be safe, with no adverse events reported during the treatment.

The study showed that patients receiving CD34+ cell therapy had significantly lower rates of unfavorable clinical outcomes (like dialysis or death) after one year compared to the control group, indicating potential efficacy in improving long-term outcomes for CKD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of intrarenal arterial autologous CD34+ cell transfusion in patients with chronic kidney disease: A randomized, open-label, controlled phase II clinical trial. Yang, CC., Sung, PH., Cheng, BC., et al.[2021]

A new automated method for purifying human natural killer (NK) cells from leukopheresis products achieved a high purity level of 91% NK cells with minimal contamination from T and B cells, making it suitable for clinical applications.

The purified NK cells demonstrated significantly enhanced natural cytotoxicity, being five times more effective than unpurified cells, and their activity can be further boosted with IL2 stimulation, suggesting a promising approach for preventing or treating complications in allogeneic bone marrow transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Purification of human natural killer cells using a clinical-scale immunomagnetic method. Iyengar, R., Handgretinger, R., Babarin-Dorner, A., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03292445

Inducing Graft Tolerance in HLA Haplotype Matched ... Collected cells will undergo CD34 selection to recover >10 million donor blood stem cells/kg of patient weight to be combined with up to 150 million donor T ...

2. withpower.com withpower.com/trial/immunological-tolerance-therapy-for-kidney-transplant-rejection-72420

Immunological Tolerance Therapy for Kidney Transplant ... This trial tests if Belumosudil can help kidney transplant patients accept their new kidney without long-term immune-suppressing drugs.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/9481712/

Isolation and infusion of donor CD34+ bone marrow cells ... Results: The infusion of CD34+ stem cells was perfectly tolerated. Five patients remained free of acute rejection at follow-up, 47-325 days post-operatively.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7723571/

Tolerance induction with donor hematopoietic stem cell ... We induced transient chimerism by combining kidney transplantation with the infusion of donor CD34+ selected hematopoietic stem cells. We present the ...

5. jci.org jci.org/articles/view/133595

Phase I trial of donor-derived modified immune cell ... Studies on CD34+ stem cell transplantation reported donor-specific unresponsiveness when persistent chimerism was established (23, 24). In HLA-identical living ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2666636721010770

Outcomes with CD34-Selected Stem Cell Boost for Poor ... Complete and overall hematologic response rates were 72% and 80%, respectively. After a median follow-up of 42 months, the actuarial survival rate was 54%.

7. academic.oup.com academic.oup.com/ndt/article-pdf/13/1/34/5190076/13-1-34.pdf

Nephrology Dialysis Transplantation Isolation and infusion ... Conclusions. Infusion of donor CD34+ stem cells in kidney transplantation is safe. The clinical usefulness of the procedure remains to be established.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7604618/

Predictors of recovery following allogeneic CD34+ ... We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03707262

Study of Combined Kidney and Blood Stem Cell Transplant ... The purpose of this study is to find out if an investigational treatment will allow kidney transplant recipients to better accept their new kidney and stop ...