Treg Therapy in Subclinical Inflammation in Kidney Transplantation (TASK)

This is an interventional treatment trial for Kidney Transplant focused on measuring graft inflammation, Treg, polyclonally expanded Tregs (polyTregs), calcineurin inhibitors (CNIs), mTOR inhibitors Read More

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