Stem Cell + Kidney Transplant for Renal Disease

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Alice Bertaina

Disqualifiers: Pregnancy, Severe cardiovascular disease, others

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

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method for performing kidney transplants in individuals with chronic kidney disease, aiming to reduce the need for lifelong medication to prevent organ rejection. The treatment combines stem cell transplants and kidney transplants from the same donor. It targets individuals with specific genetic or immune-related kidney conditions or those who have previously rejected a kidney transplant. The goal is to enhance the body's acceptance of the new kidney without long-term use of immunosuppressive drugs, which can cause serious side effects. 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 innovative approach.

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

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should be on less than 0.5 mg/kg/day of steroids, which might imply some medication adjustments.

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

Research shows that the treatments in this trial have been studied for their safety in humans. Here's a simple overview of the findings:

1. **ATG (Antithymocyte Globulin)**: Studies indicate that ATG is generally safe. It may increase infection risk, but serious side effects are uncommon.

2. **CliniMACS® Systems**: These systems remove certain cells from the blood. They are designed to be safe, but more research is needed to understand long-term effects.

3. **Cyclophosphamide**: Both doses (100 mg/Kg and 1200 mg/Kg) have been used safely in other treatments. However, the higher dose can lead to more side effects, such as heart problems.

4. **Fludarabine**: This drug is usually well-tolerated and has been used safely with low rates of severe side effects.

5. **Melphalan**: Research shows it's safe, even in high doses for certain conditions.

6. **Rituximab**: Generally safe, but it can increase infection risk, especially after a kidney transplant.

7. **Total Body Irradiation**: It can cause side effects but is considered safe when used carefully to prepare for stem cell transplants.

In this early-phase trial, researchers are still assessing safety. Based on past studies, treatments are likely to be well-tolerated, but all medications have potential risks. Anyone considering joining should weigh these risks and discuss them with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores a novel approach to treating renal disease by combining hematopoietic stem cell transplants (HSCT) with kidney transplants from the same donor. Unlike traditional treatments that rely solely on medication to manage kidney transplants, this method uses an αβdepleted HSCT to potentially promote immune tolerance, reducing the need for long-term immunosuppression. This approach might decrease the risk of rejection and the side effects associated with lifelong medication. Additionally, the trial investigates the ability to taper off pharmacological immunosuppression, which could significantly improve the quality of life for patients.

What evidence suggests that this trial's treatments could be effective for renal disease?

This trial will evaluate the use of stem cells in kidney transplants to help prevent organ rejection. Participants will receive different conditioning regimens before undergoing an αβ-depleted hematopoietic stem cell transplant (HSCT) and a subsequent kidney transplant. Research has shown that treatments like ATG (anti-thymocyte globulin) can lower the risk of rejection and improve survival rates. CliniMACS® technology removes certain immune cells, reducing the chances of graft-versus-host disease (GVHD). Cyclophosphamide has proven effective in preventing GVHD and improving overall outcomes after transplants. Rituximab increases the success of kidney transplants by targeting and reducing specific immune cells. Together, these treatments aim to eliminate the need for lifelong use of drugs that suppress the immune system, which is usually required after kidney transplants. ^{6 7 8 9 10}

Who Is on the Research Team?

Paul Grimm, MD

Principal Investigator

Stanford University

Alice Bertaina

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for patients with certain kidney diseases needing a transplant, who have moderate to severe chronic kidney disease and can consent to the study. They must be able to use birth control if of childbearing potential and match their donor in specific genetic markers. Excluded are those with significant liver dysfunction, uncontrolled medical disorders, active infections or severe heart disease.

Inclusion Criteria

I am mostly active and can do things for myself.

My kidney function is moderately to severely reduced.

Male and female subjects of childbearing potential must agree to use an effective means of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression, and if the subject experiences any cGvHD

Exclusion Criteria

My liver and kidney functions are not severely impaired.

Pregnant or lactating females

Any severe concurrent disease which, in the judgement of the investigator would place the patient at increased risk during participation in the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and HSCT

Participants undergo conditioning regimen followed by αβdepleted hematopoietic stem cell transplantation (HSCT)

6 weeks

Multiple visits for conditioning and transplantation

Post-HSCT Monitoring

Monitoring for donor myeloid engraftment and acute GvHD

3 months

Regular visits for lab tests and monitoring

Kidney Transplantation (KT)

Participants undergo kidney transplantation from the same donor as HSCT

1 week

In-patient procedure with follow-up visits

Post-KT Monitoring

Monitoring for kidney function and tapering of immunosuppression

3 months

Regular visits for kidney function tests and monitoring

Follow-up

Participants are monitored for long-term outcomes including chronic GvHD and kidney function

1 year

Periodic visits for long-term monitoring

What Are the Treatments Tested in This Trial?

Interventions

• ATG
• CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System
• Cyclophosphamide 100 mg/Kg
• Cyclophosphamide 1200 mg/Kg
• Fludarabine
• Kidney Transplant
• Melphalan
• Rituximab
• Total Body Irradiation

Trial Overview The trial tests whether a sequence of stem cell transplantation (using αβ T-cell depletion) followed by a kidney transplant from the same donor can prevent organ rejection without lifelong immunosuppression drugs. It's an early-phase study at one center without randomization or control groups.

How Is the Trial Designed?

Group I: Cohort 2a: Conditioning Regimen B Experimental Treatment 8 Interventions

If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.

Group II: Cohort 2a: Conditioning Regimen A Experimental Treatment 7 Interventions

If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.

Group III: Cohort 1b: Conditioning Regimen B Experimental Treatment 8 Interventions

An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.

Group IV: Cohort 1b: Conditioning Regimen A Experimental Treatment 7 Interventions

An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.

ATG is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Thymoglobulin for:

• Prevention and treatment of acute rejection in patients undergoing kidney transplantation
• Treatment of aplastic anemia in patients who are not candidates for bone marrow transplantation

Approved in European Union as Thymoglobulin for:

• Prevention and treatment of acute rejection in patients undergoing kidney transplantation
• Treatment of aplastic anemia in patients who are not candidates for bone marrow transplantation

Approved in Canada as Thymoglobulin for:

• Prevention and treatment of acute rejection in patients undergoing kidney transplantation
• Treatment of aplastic anemia in patients who are not candidates for bone marrow transplantation

Who Is Running the Clinical Trial?

Alice Bertaina

Lead Sponsor

Trials

2

Recruited

170+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Published Research Related to This Trial

Kidney transplant patients treated with anti-thymocyte globulin (ATG) show signs of immunosenescence, including an increase in specific T cell markers (CD28-, CD85j+, CD57+) and a decrease in T cell receptor (TCR) diversity, compared to untreated patients.

Despite these changes, ATG-treated patients maintain T cell proliferation and cytokine production capabilities, indicating that while ATG may lead to long-term immune changes, it does not completely impair T cell function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-thymocyte globulin-mediated immunosenescent alterations of T cells in kidney transplant patients. Lee, GH., Lee, JY., Jang, J., et al.[2022]

A retrospective review of 83 renal transplant patients showed that equine anti-thymocyte globulin (Atgam) can be safely administered via peripheral veins without significant complications, such as phlebitis or symptomatic venous thrombosis.

Only mild reactions like edema or erythema occurred in two patients, which were easily managed, indicating that peripheral vein infusion is a safe and convenient alternative to central line administration for ATG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of equine anti-thymocyte globulin via peripheral vein in renal transplant recipients. Rahman, GF., Hardy, MA., Cohen, DJ.[2019]

In a study comparing two immunosuppressive drugs, MALG and ATGAM, in first renal transplants, both were found to be equally effective in depleting T cells and preventing rejection, with similar rates of rejection and anti-horse antibodies among patients.

Early renal function was better with MALG compared to ATGAM, but by two weeks post-transplant, both groups showed similar renal function, indicating that while MALG may provide a short-term advantage, both drugs ultimately have comparable long-term efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Minnesota antilymphoblast globulin and Upjohn antithymocyte globulin for induction immunosuppression of human renal allografts. Pescovitz, MD., Book, BK., Milgrom, ML., et al.[2010]

Thymoglobulin treatment in adult renal transplant recipients resulted in significantly lower rates of acute rejection (4%) compared to Atgam (25%) after one year, indicating better efficacy for Thymoglobulin.

While Thymoglobulin was associated with more frequent early leukopenia, it led to fewer serious adverse events and better overall event-free survival (94% vs. 63% for Atgam), suggesting a safer profile despite the lymphocyte count reduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Brennan, DC., Flavin, K., Lowell, JA., et al.[2022]

In a study of 289 renal transplant recipients, the use of Thymoglobulin, ATG Fresenius, and Simulect as induction therapies showed similar efficacy in preventing acute rejection and ensuring patient and graft survival in both expanded criteria donation (ECD) and donation after cardiac death (DCD) groups.

Despite higher rates of leukopenia and thrombopenia in the ECD group treated with polyclonal induction, there were no significant differences in overall costs between ECD and DCD transplantations, indicating that both induction therapies can be effectively used without impacting financial outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polyclonal versus monoclonal induction therapy in a calcineurin inhibitor-free immunosuppressive therapy in renal transplantation: a comparison of efficacy and costs. Sánchez-Escuredo, A., Alsina, A., Diekmann, F., et al.[2021]

In a study comparing 90 kidney transplant patients, those receiving Thymoglobuline (TG) alongside conventional drugs experienced fewer signs of rejection and lower creatinine levels, indicating better graft function compared to those on conventional therapy alone.

While urinary tract infections were more common in the TG group, the overall incidence of infections and treatment costs were similar between both groups, suggesting TG is a beneficial addition to standard immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding thymoglobuline to the conventional immunosuppressant regimen in kidney transplantation: A cost-benefit analysis. Oliaei, F., Akbari, R., Ghazi Mirsaeid, AM.[2021]

In a study involving 163 renal transplant patients, Thymoglobulin was more effective than Atgam in reversing acute rejection, achieving an 88% rejection reversal rate compared to 76% for Atgam.

Thymoglobulin also demonstrated a lower rate of recurrent rejection at 90 days (17% vs. 36% for Atgam), while both treatments had similar safety profiles and long-term survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Gaber, AO., First, MR., Tesi, RJ., et al.[2019]

Thymoglobulin may offer better protection against acute rejection and improve patient and graft survival compared to ATG-F, but it is associated with a higher risk of cytomegalovirus infections and post-transplant malignancies.

Both Thymoglobulin and ATG-F have distinct side effects, with Thymoglobulin causing more leukocyte depletion and delayed recovery, while ATG-F leads to greater reductions in platelet and erythrocyte counts, necessitating additional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review on comparing two commonly used rabbit anti-thymocyte globulins as induction therapy in solid organ transplantation. Gharekhani, A., Entezari-Maleki, T., Dashti-Khavidaki, S., et al.[2013]

In a study of 236 kidney transplant recipients, those who received thymoglobulin experienced higher rates of delayed graft function compared to those who received ATGAM, indicating a potential drawback of thymoglobulin despite its overall better long-term graft survival.

Thymoglobulin induction showed better death-censored graft survival than ATGAM, highlighting its efficacy as an induction agent, while bacterial infections were identified as a significant risk factor for graft failure, emphasizing the need for infection prevention in transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison between thymoglobulin and ATGAM as an induction agent in adult kidney transplantation: a single-center experience. Kim, JM., Jang, HR., Ko, JS., et al.[2016]

Tacrolimus significantly improves graft survival and reduces the risk of acute rejection in kidney transplant recipients compared to cyclosporin, with a relative risk of graft loss at six months being 0.56 based on data from 4102 patients across 30 trials.

While tacrolimus is more effective, it is associated with a higher risk of developing insulin-requiring diabetes and other side effects like tremors and gastrointestinal issues, indicating a trade-off between efficacy and safety in post-transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Webster, A., Woodroffe, RC., Taylor, RS., et al.[2022]

In a study of 309 kidney transplant recipients, those treated with ATG-F required significantly more red blood cell (RBC) transfusions compared to those treated with Thymoglobulin (63.3% vs. 46%), indicating a higher risk associated with ATG-F induction therapy.

Despite the increased need for RBC transfusions in the ATG-F group, there were no differences in patient survival rates, acute rejection incidents, or infections, suggesting that while ATG-F may pose a risk for early transfusion, it does not adversely affect overall transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATG-Fresenius increases the risk of red blood cell transfusion after kidney transplantation. Sebti, M., Petit-Hoang, C., Chami, B., et al.[2023]

In a study of 31 kidney transplant recipients treated with antithymocyte globulin (ATG) during the COVID-19 pandemic, the use of ATG was found to be safe, with an acceptable risk of adverse events, including mild thrombocytopenia and infectious complications.

Patients receiving ATG experienced a higher rate of infectious complications compared to those treated with basiliximab (32.3% vs 10.2%), but kidney graft function remained comparable between the two groups up to 12 months post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Antithymocyte Globulin Use in Kidney Graft Recipients During the COVID-19 Pandemic. Kolonko, A., Więcek, A.[2021]

Citations

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Outcomes of Antithymocyte Globulin-Post-Transplantation ... ATG(2)/PTCy prophylaxis effectively prevents GVHD and is associated with comparable relapse risk, OS, and GRFS as seen with ATG(4.5)/PTCy and ATG-based ...

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Efficacy and Safety of Combining r‐ATG With PTCy for ... Rabbit anti‐thymocyte globulin (r‐ATG) or post‐transplant cyclophosphamide (PTCy) is effective in reducing GvHD in haploidentical‐HSCT.