Treg Therapy in Subclinical Inflammation in Kidney Transplantation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Treg Adoptive Therapy in Subclinical Inflammation in Kidney Transplantation (CTOT-21)

Conditions
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Kidney Transplant, Adult Living Donor Kidney Transplant Recipients, Renal Transplant, Living Kidney Donor

Intervention / Treatment
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* Biological: Polyclonal Regulatory T Cells
* Drug: Everolimus
* Drug: Tacrolimus
* Drug: Mycophenolate mofetil
* Drug: Mycophenolic acid
* Drug: Acetaminophen
* Drug: Diphenhydramine
* Procedure: Biopsy, Kidney
* Procedure: Blood Draw
* Procedure: Leukapheresis
* Procedure: IS regimen conversion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals who meet all of the following criteria are eligible for enrollment as study participants: Subject must be able to understand and provide informed consent; Age ≥18 years of age at the time of study entry; Recipients of non- Human Leukocyte Antigen (HLA) identical living or deceased renal transplants; 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). Estimated glomerular filtration rate (eGFR) ≥30 ml/min at the time of study entry; Maintenance immunosuppression consisting of tacrolimus, MMF/MPA (≥1000 mg/720 mg daily) ± prednisone (≤10 mg/day); 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; Documented Hepatitis B (HB) serologies must be: Positive HB surface antibody, negative HB core antibody and negative HB surface antigen for recipients immune to hepatitis B 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. 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. 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 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: Individuals randomized to the polyTreg and darTreg groups who continue to meet all of the enrollment criteria; and 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: Received at least 300 x 10^6 polyTreg infusion; 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: Inability or unwillingness of a participant to give written informed consent or comply with study protocol; History of malignancy; except adequately treated basal cell carcinoma; History of graft loss from acute rejection within 1 year after any previous transplant; History of transplant renal artery stenosis; 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; Known hypersensitivity to mTOR inhibitors or contraindication to everolimus (including history of wound healing complications); Any chronic illness requiring uninterrupted anti-coagulation after kidney transplantation; 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. Positive HIV 1 or HIV 2 serology prior to transplantation; Positive HBSAg or HBcAb serology; Proteinuria with urine protein-to-creatinine ratio > 1.0 g/g; Any condition requiring chronic use of corticosteroids >10mg/day at the time of study entry; Subjects requiring treatment for pathologic findings on study eligibility biopsy (see inclusion 5). Active infection at the time of study entry; History of active TB or latent TB without adequate treatment; Serum BK virus >1,000 copies/ml by Polymerase Chain Reaction (PCR) at the time of study entry; Hematocrit <27%; Absolute Neutrophil Count (ANC) < 1,000/μL; and/or lymphocyte count <500/μL at the time of study entry; Participation in any other studies with investigational drugs or regimens in the preceding year; Any condition or prior treatment which, in the opinion of the investigator, precludes study participation. Unable to provide adequate biopsy specimen (paraffin embedded formalin fixed) from eligibility biopsy (3-7 months post -transplant) for quantitative analysis. 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. 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. 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: Received any vaccination within 14 days prior to blood collection for Treg manufacture; Unacceptable Treg product; Positive pregnancy test for women of child bearing potential. mTOR Conversion Exclusion Criteria: Post-transplant Donor-Specific Antibodies (DSA) >2000 mean florescence intensity (MFI). Any condition or clinical variable, which in the opinion of the site investigator, precludes conversion to mTOR

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Maintenance CNI based immunosuppression therapy group<br>Standard of care (N=7 participants in this group) | Drug: Tacrolimus<br> <br> * Other names: Prograf;Drug: Mycophenolate mofetil<br>* All enrolled participants will be on MMF (or MPA below) at the time of study entry at a minimum dose of 1000mg per day.<br>* Other names: MMF;Drug: Mycophenolic acid<br>* All enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day.<br>* Other names: MPA;Procedure: Biopsy, Kidney<br> <br> * Other names: Kidney Biopsy;Procedure: Blood Draw<br> <br> * Other names: Venipuncture;|
| Experimental: Polyclonal Regulatory T Cells group<br>Subjects to receive polyTregs (550 ± 450 x 10^6). After receiving at least 300X10^6 polyTregs infusion, eligible subjects will start mammalian Target of Rapamycin (mTOR) inhibitor. Target tacrolimus trough levels prior to conversion to everolimus are 4-11 μg/dl, which falls within standard of care. For eligible participants in polyTregs and darTregs groups, the tacrolimus dose will be reduced by 50% when everolimus is initiated. Tacrolimus will be discontinued 4 weeks after initiation of everolimus therapy. Everolimus, a mTOR inhibitor immunosuppressant, will be initiated at a dose of 1.5 mg orally twice daily and titrated, as needed. Participants will begin everolimus with target trough levels of 3-8μg/L for 4 weeks while still taking tacrolimus. Everolimus target trough levels will be 6-10 μg/L when tacrolimus is discontinued. (N=7 participants in this group) | Biological: Polyclonal Regulatory T Cells<br>* Participants randomized to polyTregs group will receive a single infusion of 550 ± 450 x 10^6 polyTregs.<br>* Other names: polyTregs;Drug: Everolimus<br> <br> * Other names: Zortress;Drug: Tacrolimus<br> <br> * Other names: Prograf;Drug: Mycophenolate mofetil<br>* All enrolled participants will be on MMF (or MPA below) at the time of study entry at a minimum dose of 1000mg per day.<br>* Other names: MMF;Drug: Mycophenolic acid<br>* All enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day.<br>* Other names: MPA;Drug: Acetaminophen<br>* 650 mg acetaminophen, administered 30-60 minutes prior to infusion as pre-medication.<br>* Other names: Tylenol;Drug: Diphenhydramine<br>* 25-50 mg diphenhydramine intravenously or by mouth, administered 30-60 minutes prior to infusion as pre-medication.<br>* Other names: Benadryl;Procedure: Biopsy, Kidney<br> <br> * Other names: Kidney Biopsy;Procedure: Blood Draw<br> <br> * Other names: Venipuncture;Procedure: Leukapheresis<br> <br> * Other names: leukocytapheresis;Procedure: IS regimen conversion<br>* Conversion from Tacrolimus, a calcineurin inhibitors (CNI), to Everolimus, an mTOR inhibitor.<br>* Other names: Everolimus Conversion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Banff 2A or higher acute cell-mediated rejection and/or acute antibody mediated rejection | The safety of polyTregs will be described in comparison with CNI-based maintenance IS therapy. | Baseline (Day 0) to Day 405 | 
| Timing of Banff 2A or higher acute cell-mediated rejection and/or acute antibody mediated rejection | The safety of polyTregs will be described in comparison with CNI-based maintenance IS therapy. | Baseline (Day 0) to Day 405 | 
| Incidence of study defined Grade 3 or higher infection | The safety of polyTregs will be described in comparison with CNI-based maintenance IS therapy. | Baseline (Day 0) to Day 405 | 
| Timing of study defined Grade 3 or higher infection | The safety of polyTregs will be described in comparison with CNI-based maintenance IS therapy. | Baseline (Day 0) to Day 405 | 
| Percent change in inflammation | As measured by the percentage area of cortex occupied by inflammatory cells using computer-assisted quantitative image analysis on the biopsy, expressed as the percent change relative to the baseline biopsy. | Baseline and 7 months after study group allocation | 
| Immunologic profiles of kidney transplant recipients | Immunologic profiles using the common response module (CRM) graft gene expression of rejection and/or histologic evidence of inflammation in biopsies. | At 2 weeks after infusion (PolyTregs group) and 7 months after group allocation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of polyTregs infusion reactions | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Severity of polyTregs infusion reactions | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Timing of polyTregs infusion reactions | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Incidence of culture-proven and clinically diagnosed infection. | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Severity of culture-proven and clinically diagnosed infection | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Timing of culture-proven and clinically diagnosed infection | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Incidence of acute rejection using Banff grading | To assess safety of PolyTregs. Banff 2007 Type 1A or higher and clinical treatment for acute rejection. Central reading will be utilized when accounting for study stopping rule and for safety endpoint. | Baseline (Day 0) to Day 405 | 
| Severity of acute rejection using Banff grading | To assess safety of PolyTregs. Banff 2007 Type 2A or higher and clinical treatment for acute rejection. Central reading will be utilized when accounting for study stopping rule and for safety endpoint. | Baseline (Day 0) to Day 405 | 
| Timing of acute rejection using Banff grading | To assess safety of PolyTregs. Banff 2007 Type 1A or higher and clinical treatment for acute rejection. Central reading will be utilized when accounting for study stopping rule and for safety endpoint. | Baseline (Day 0) to Day 405 | 
| Incidence of BK viremia | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Timing of BK viremia | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Incidence of cytomegalovirus (CMV) reactivation | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Timing of CMV reactivation | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Incidence of > 10% decrease in estimated Glomerular Filtration Rate (eGFR) compared to baseline | To assess safety of PolyTregs. | Baseline (Day 0) to Day 405 | 
| Timing of > 10% decrease in eGFR compared to baseline | To assess safety of PolyTregs . | Baseline (Day 0) to Day 405 | 
| Incidence of acute rejection after converting to mTor therapy following polyTregs infusion | To assess safety of mTOR therapy after Treg infusion. Subjects who receive Tregs in either group who convert to mTOR therapy will be compared to subjects who did not convert to mTOR therapy; as well as subjects in CNI Maintenance group. | Day 69 to Day 405 | 
| Timing of acute rejection after converting to mTor therapy following polyTregs infusion | To assess safety of mTOR therapy after Treg infusion. Subjects who receive Tregs in either group who convert to mTOR therapy will be compared to subjects who did not convert to mTOR therapy; as well as subjects in CNI Maintenance group. | Day 69 to Day 405 | 
| Proportion of participants exhibiting >=25% relative decrease of inflammation between baseline kidney biopsy and the week 2 kidney biopsy | Measured as the percentage area of cortex occupied by inflammatory cells using computer-assisted quantitative image analysis on the baseline kidney biopsy and the biopsy 2 weeks after polyTregs. | Baseline to 2 weeks after polyTregs | 
| Proportion of participants exhibiting >=50% relative decrease of inflammation between baseline kidney biopsy and the week 2 kidney biopsy |  | Baseline to 2 weeks after polyTregs | 
| Proportion of participants exhibiting >=25% relative decrease of inflammation between baseline kidney biopsy and the 6 month kidney biopsy |  | Baseline to 7 months after group allocation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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polyclonally expanded Tregs (polyTregs), calcineurin inhibitors (CNIs), mTOR inhibitors, graft inflammation, Treg