Stem Cell + Kidney Transplant for Renal Disease

Overseen by Paul Grimm, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Alice Bertaina

Disqualifiers: Pregnancy, Severe cardiovascular disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a special stem cell transplant followed by a kidney transplant in patients who need a new kidney. The goal is to prevent kidney rejection without lifelong medication by preparing the immune system to accept the new kidney.

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.

What data supports the effectiveness of the treatment for renal disease?

Research shows that Thymoglobulin, a component of the treatment, is effective in reducing acute rejection episodes in kidney transplant patients when compared to Atgam, another similar drug. This suggests that Thymoglobulin can be a beneficial part of the treatment for renal disease. ^{1 2 3 4 5}

Is the treatment involving Thymoglobulin and ATG safe for kidney transplant patients?

Studies have shown that Thymoglobulin and ATG, used in kidney transplants, can cause mild side effects like low platelet counts (thrombocytopenia) and increased risk of infections, especially during the COVID-19 pandemic. However, these treatments are generally considered safe for use in kidney transplant patients. ^{2 6 7 8 9}

What makes this kidney transplant treatment unique?

This treatment is unique because it combines a kidney transplant with stem cell therapy and a range of immunosuppressive drugs, including anti-thymocyte globulin (ATG), which helps prevent the body from rejecting the new kidney. The use of stem cells and specific immunosuppressants like ATG and Rituximab is designed to improve transplant success and reduce rejection risk, which is different from standard treatments that typically rely on a combination of calcineurin inhibitors, anti-proliferative agents, and steroids. ^{2 3 10 11 12}

Research Team

Alice Bertaina

Principal Investigator

Stanford University

Paul Grimm, MD

Principal Investigator

Stanford University

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• ATG (Antibody)
• CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System (Cell Therapy)
• Cyclophosphamide 100 mg/Kg (Alkylating agents)
• Cyclophosphamide 1200 mg/Kg (Alkylating agents)
• Fludarabine (Anti-metabolites)
• Kidney Transplant (Procedure)
• Melphalan (Alkylating agents)
• Rituximab (Monoclonal Antibodies)
• Total Body Irradiation (Radiation)

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.

Participant Groups

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 Canada for the following indications:

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+

Jonathan Thomas

California Institute for Regenerative Medicine (CIRM)

Chief Executive Officer

BA in Biology and History from Yale University, JD from Yale Law School, PhD in Commonwealth History from Oxford University

Rosa Canet-Avilés

California Institute for Regenerative Medicine (CIRM)

Chief Medical Officer since 2024

PhD in Neuroscience from Leeds University, BS in Organic Chemistry from Central University of Barcelona

Findings from Research

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 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 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]

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]

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]

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]

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]

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 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]

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]

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]

References

1. United States 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. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. [2022]

3. Iran pubmed.ncbi.nlm.nih.gov

Adding thymoglobuline to the conventional immunosuppressant regimen in kidney transplantation: A cost-benefit analysis. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Administration of equine anti-thymocyte globulin via peripheral vein in renal transplant recipients. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Comparison of Minnesota antilymphoblast globulin and Upjohn antithymocyte globulin for induction immunosuppression of human renal allografts. [2010]

6. United States pubmed.ncbi.nlm.nih.gov

Comparison between thymoglobulin and ATGAM as an induction agent in adult kidney transplantation: a single-center experience. [2016]

7. United States pubmed.ncbi.nlm.nih.gov

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

8. United States 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. [2021]

9. England pubmed.ncbi.nlm.nih.gov

A review on comparing two commonly used rabbit anti-thymocyte globulins as induction therapy in solid organ transplantation. [2013]

10. Switzerland pubmed.ncbi.nlm.nih.gov

ATG-Fresenius increases the risk of red blood cell transfusion after kidney transplantation. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. [2022]

12. Australia pubmed.ncbi.nlm.nih.gov

Anti-thymocyte globulin-mediated immunosenescent alterations of T cells in kidney transplant patients. [2022]