Treg Therapy in Subclinical Inflammation in Kidney Transplantation

National Institute of Allergy and Infectious Diseases (NIAID)32 enrolled

Overview

The purpose of this study is: * To see if polyTregs can reduce inflammation in a transplanted kidney. * To find out what effects, good or bad, polyTregs will have in the kidney recipient. * To find out what effects, good or bad, taking everolimus after polyTregs will have in the kidney recipient.

Inflammation occurs when the body's defense system recognizes a foreign object (such as a transplanted kidney), and responds by sending white blood cells to attack the foreign object. These cells and the substances they produce can damage the transplanted kidney. There is currently no standard treatment for inflammation in the kidney; some transplant centers do not treat inflammation at all. Rejection is a more severe form of inflammation and injury. Both inflammation and rejection are diagnosed by looking at a piece of kidney (a kidney biopsy) under a microscope. Kidneys that have inflammation and/or rejection do not work as well or last as long as kidneys without injury. People who have a transplant take immunosuppressive drugs (IS) to prevent inflammation and rejection. Although kidney transplant recipients usually do well in the first five years after transplant, transplant researchers are interested in finding ways to prevent inflammation and rejection without IS, or with lower doses of IS in order to avoid side effects. While some white blood cells cause inflammation, other types of white blood cells, called T regulatory cells (Tregs), can control inflammation. Tregs may have an important role in controlling or preventing inflammation and rejection. A person's Tregs can be grown in the laboratory to increase their number (polyTreg). These Tregs can be given back through a needle placed in a vein (IV). PolyTregs, when given to the recipient, might reduce inflammation in the transplanted kidney. However, this effect has not yet been shown. One of the IS drugs used in kidney transplant is Everolimus. Everolimus has been shown to help Tregs survive better than other types of IS drugs. This is a randomized open-label trial to determine the safety and efficacy of a single dose of autologous polyTregs in renal transplant recipients with subclinical inflammation (SCI) in the 3 to 7 months post-transplant allograft protocol biopsy compared to control patients treated with CNI-based immunosuppression. The efficacy of the Treg therapy will be assessed by the reduction of graft inflammation on biopsies performed at 7 months after study group allocation compared to the eligibility biopsy.

Study Type

INTERVENTIONAL

Allocation

Conditions

Kidney Transplant Adult Living Donor Kidney Transplant Recipients Renal Transplant Living Kidney Donor

Interventions

Polyclonal Regulatory T CellsBIOLOGICAL

Participants randomized to polyTregs group will receive a single infusion of 550 ± 450 x 10\^6 polyTregs.

EverolimusDRUG

TacrolimusDRUG

Mycophenolate mofetil

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: Individuals who meet all of the following criteria are eligible for enrollment as study participants: 1. Subject must be able to understand and provide informed consent; 2. Age ≥18 years of age at the time of study entry; 3. Recipients of non- Human Leukocyte Antigen (HLA) identical living or deceased renal transplants; 4. Protocol renal allograft biopsy at 5 months (± 8 weeks) after transplantation with Banff i1 and/or ti1 with concomitant t scores t0, t1,t2 or t3; Banff i2 and/or ti2 with concomitant t scores t0 or t1; and without v \> 0, \[ptc + g\] ≥2, C4d \>1 (by immunofluorescence, IF), or C4d \> 0 (by immunohistochemistry, IHC); confirmed by central pathologist. Subjects must not be treated for pathologic criteria (e.g. steroids). 5. Estimated glomerular filtration rate (eGFR) ≥30 ml/min at the time of study entry; 6. Maintenance immunosuppression consisting of tacrolimus, MMF/MPA (≥1000 mg/720 mg daily) ± prednisone (≤10 mg/day); 7. Current immunizations including TdAP, hepatitis B, pneumococcal and seasonal influenza vaccines prior to study treatment, completed prior to randomization and no less than 14 days prior to planned manufacturing collection; 8. Documented Hepatitis B (HB) serologies must be: 1. Positive HB surface antibody, negative HB core antibody and negative HB surface antigen for recipients immune to hepatitis B 2. Negative HB surface antibody, negative HB core antibody and negative HB surface antigen for non-immune/ HBV naïve recipients provided donor had negative HB core antibody and negative HB surface antigen at the time of donation. 9. Negative TB test (PPD, interferon-gamma release assay, ELISPOT testing) within 1 year prior to enrollment. Subjects with a history of TB (positive TB test without active infection) must have completed one of the latent TB infection treatment regimens endorsed by the CDC (Division of TB Elimination, 2016). Alternative regimens for latent TB infection eradication will be adjudicated by the site's infectious disease specialist. 10. Female subjects of childbearing potential must have reviewed the Mycophenolate Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) and have a negative pregnancy test upon study entry (Reference:https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm318880.htm); and 11. Female subjects with child-bearing potential, must agree to use FDA approved methods of birth control for the duration of the study; subjects must consult with their physician and determine the most suitable method(s) that are greater than 80% effective (http://www.fda.gov/birthcontrol). Treg Infusion Inclusion Criteria: 1. Individuals randomized to the polyTreg and darTreg groups who continue to meet all of the enrollment criteria; and 2. Negative SARS-COV2 by RTP-PCR testing within 1 week of Treg infusion. mTOR Conversion Inclusion Criteria: Individuals who meet all of these criteria are eligible for mTOR conversion: 1. Received at least 300 x 10\^6 polyTreg infusion; 2. Resolution of inflammation on the 2 week post-infusion biopsy as compared to the baseline biopsy, confirmed by central pathologist. Exclusion Criteria: Individuals who meet any of these criteria are not eligible for enrollment as study participants: 1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol; 2. History of malignancy; except adequately treated basal cell carcinoma; 3. History of graft loss from acute rejection within 1 year after any previous transplant; 4. History of transplant renal artery stenosis; 5. History of cellular rejection prior to enrollment that did not respond to steroids and/or subsequent creatinine after treatment for rejection greater than 15% above baseline; 6. Known hypersensitivity to mTOR inhibitors or contraindication to everolimus (including history of wound healing complications); 7. Any chronic illness requiring uninterrupted anti-coagulation after kidney transplantation; 8. Post-transplant DSA \>5000 MFI or post-transplant treatment with IVIg for DSA. * Note: Enrolled subjects with post-transplant DSA \>2000 MFI will not be eligible for mTOR conversion. 9. Positive HIV 1 or HIV 2 serology prior to transplantation; 10. Positive HBSAg or HBcAb serology; 11. Proteinuria with urine protein-to-creatinine ratio \> 1.0 g/g; 12. Any condition requiring chronic use of corticosteroids \>10mg/day at the time of study entry; 13. Subjects requiring treatment for pathologic findings on study eligibility biopsy (see inclusion 5). 14. Active infection at the time of study entry; 15. History of active TB or latent TB without adequate treatment; 16. Serum BK virus \>1,000 copies/ml by Polymerase Chain Reaction (PCR) at the time of study entry; 17. Hematocrit \<27%; Absolute Neutrophil Count (ANC) \< 1,000/μL; and/or lymphocyte count \<500/μL at the time of study entry; 18. Participation in any other studies with investigational drugs or regimens in the preceding year; 19. Any condition or prior treatment which, in the opinion of the investigator, precludes study participation. 20. Unable to provide adequate biopsy specimen (paraffin embedded formalin fixed) from eligibility biopsy (3-7 months post -transplant) for quantitative analysis. 21. Epstein-Barr virus (EBV) naïve recipient of a kidney from an EBV positive donor; and/or historically EBV naïve recipient with primary EBV infection at the time of screening (e.g., anti-VCA IgM positive and EBNA negative), a positive EBV PCR. 22. Hepatitis C Virus AB positive subjects with negative HCV PCR are eligible if they have spontaneously cleared infection or are in sustained virologic remission for at least 12 weeks after treatment. 23. Positive SARS-CoV2 testing by RT-PCR Treg Infusion Exclusion Criteria: Individuals randomized to polyTreg and darTreg groups who meet any of these criteria are not eligible for Treg infusion: 1. Received any vaccination within 14 days prior to blood collection for Treg manufacture; 2. Unacceptable Treg product; 3. Positive pregnancy test for women of child bearing potential. mTOR Conversion Exclusion Criteria: 1. Post-transplant Donor-Specific Antibodies (DSA) \>2000 mean florescence intensity (MFI). 2. Any condition or clinical variable, which in the opinion of the site investigator, precludes conversion to mTOR

Locations (6)

University of Alabama, Birmingham

Birmingham, Alabama, United States

University of California at San Francisco

San Francisco, California, United States

University of Colorado Health Transplant Center - Anschutz

Aurora, Colorado, United States

Northwestern University Comprehensive Transplant Center

Chicago, Illinois, United States

Outcomes

Primary Outcomes

Incidence of Banff 2A or Higher Acute Cell-mediated Rejection and/or Acute Antibody Mediated Rejection

Acute cell-mediated rejection was defined using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to 2A were determined to have met the endpoint. Severity is graded as 1A, 1B, 2A, 2B, or 3, with 1A being the mildest form of cellular rejection and 3 being the most severe form of cellular rejection. Antibody mediated rejection was defined as diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury.

Time frame: 405 days post-group allocation

Timing of Banff 2A or Higher Acute Cell-mediated Rejection and/or Acute Antibody Mediated Rejection

Acute cell-mediated rejection was defined using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to 2A were determined to have met the endpoint. Severity is graded as 1A, 1B, 2IA, 2IB, or 3, with 1A being the mildest form of cellular rejection and 3 being the most severe form of cellular rejection. Antibody mediated rejection was defined as diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury.

Time frame: 405 days post-group allocation

Incidence of Study Defined Grade 3 or Higher Infection

This outcome measure includes infections reported as adverse events. Severe infection was defined in the study as a Grade 3 or higher infection. Severity is graded as 1 through 5, with 1 being least severe to 5 being most severe. Grade 3 is any infection associated with hemodynamic compromise requiring pressors; any infection necessitating ICU level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection. Grade 4 is any life-threatening infection. Grade 5 is any infection resulting in death.

Time frame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups

Data from ClinicalTrials.gov

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Secondary Outcomes

Incidence of polyTregs Infusion Reactions

An infusion reaction is characterized by an adverse reaction to the infusion of pharmacological substance, as defined using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 set forth by the National Cancer Institute.

Time frame: 365 days after Treg infusion for the participants in the polyTregs group

Severity of polyTregs Infusion Reactions

Severity of infusion reactions were defined using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 set forth by the National Cancer Institute. Severity of adverse events is graded as 1 through 5, with 1 being least severe to 5 being most severe.

Time frame: 365 days after Treg infusion for the participants in the polyTregs group

Timing of polyTregs Infusion Reactions

Time frame: 365 days after Treg infusion for the participants in the polyTregs group

Incidence of Culture-proven and Clinically Diagnosed Infection.

A culture-proven and clinically diagnosed infection in this study was defined as any locally reported infection due to bacterial organism, due to fungal organism, due to CMV, or which met adverse event criteria, except for COVID-19.

Time frame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups

Severity of Culture-proven and Clinically Diagnosed Infection

A culture-proven and clinically diagnosed infection was defined as any locally reported infection due to bacterial organism, fungal organism, CMV, or which met adverse event criteria, except for COVID-19. Severe infection was defined in the study as a Grade 3 or higher infection. Severity is graded as 1 through 5 with 1 being least severe to 5 being most severe. Grade 3 is any infection associated with hemodynamic compromise requiring pressors; any infection necessitating ICU level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection. Grade 4 is any life-threatening infection. Grade 5 is any infection resulting in death. If a culture proven and clinically diagnosed infection did not qualify for AE reporting, then it did not have a severity grade.

Time frame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups

Timing of Culture-proven and Clinically Diagnosed Infection

A culture-proven and clinically diagnosed infection in this study was defined as any locally reported infection due to bacterial organism, fungal organism, CMV, or which met adverse event criteria, except for COVID-19.

Time frame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups

Incidence of Acute Rejection Using Banff Grading

Acute cell-mediated rejection was defined using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to 1A were determined to have met the endpoint. Severity is graded as 1A, 1B, 2A, 2B, or 3, with 1A being the mildest form of cellular rejection and 3 being the most severe form of cellular rejection.

Time frame: 405 days post-group allocation

Severity of Acute Rejection Using Banff Grading

Time frame: 405 days post-group allocation

Timing of Acute Rejection Using Banff Grading

Time frame: 405 days post-group allocation

Incidence of BK Viremia

BK viremia was determined using locally reported serum PCR results. PCR results reported as positive and \>0 copies/mL were considered as meeting the endpoint. Only positive results following Treg infusion were considered for participants in the polyTregs and darTregs groups.

Time frame: 405 days post-group allocation

Timing of BK Viremia

Time frame: 405 days post-group allocation

Incidence of Cytomegalovirus (CMV) Reactivation

CMV reactivation was defined as CMV viremia and determined using locally reported serum, plasma, or whole blood PCR results. PCR results reported as \>0 IU/mL were considered as meeting the endpoint. Only positive results following Treg infusion were considered for participants in the polyTregs and darTregs groups.

Time frame: 405 days post-group allocation

Timing of CMV Reactivation

Time frame: 405 days post-group allocation

Incidence of > 10% Decrease in Estimated Glomerular Filtration Rate (eGFR) Compared to Baseline

Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 2021 equation. A value of 90+ means kidney function is normal. A value between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. Values between 30 and 59 indicate moderately reduced kidney function. Values between 15 and 29 indicate severely reduced kidney function. Values below 15 indicate very severe or end stage kidney failure. The percent change in eGFR was calculated at each post-baseline timepoint as \[(post-baseline eGFR minus baseline (i.e., screening) eGFR) divided by baseline eGFR\] multiplied by 100 and rounded to the nearest hundredth for each participant. A participant was considered to have met the endpoint if at least one instance of a greater than 10% decrease from baseline was observed.

Time frame: 405 days post-group allocation

Timing of > 10% Decrease in eGFR Compared to Baseline

Time frame: 405 days post-group allocation

Incidence of Acute Rejection After Converting to mTOR Therapy Following polyTregs Infusion

Time frame: 69 days post-group allocation to 405 days post-group allocation

Timing of Acute Rejection After Converting to mTOR Therapy Following polyTregs Infusion

Time frame: 69 days post-group allocation to 405 days post-group allocation

Proportion of Participants Exhibiting >=25% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the Week 2 Kidney Biopsy

The change in inflammation was measured by the percentage area of the renal cortex occupied by inflammatory cells on biopsy 2 weeks after polyTregs infusion. This change was expressed as the percent change relative to the baseline biopsy. The measurements were obtained using computer-assisted quantitative image analysis.

Time frame: Baseline biopsy to week 2 kidney biopsy

Proportion of Participants Exhibiting >=50% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the Week 2 Kidney Biopsy

Time frame: Baseline biopsy to week 2 kidney biopsy

Proportion of Participants Exhibiting >=25% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the 6 Month Kidney Biopsy

The change in inflammation was measured by the percentage area of the renal cortex occupied by inflammatory cells on biopsy 7 months after study group allocation. This change was expressed as the percent change relative to the baseline biopsy. The measurements were obtained using computer-assisted quantitative image analysis.

Time frame: Baseline biopsy to 7 months post-group allocation