Treg Adoptive Therapy for Subclinical Inflammation in Kidney Transplantation

A Pilot Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy in Renal Transplant Recipients

The purpose of this study is to test the safety of the experimental therapy of a single infusion of Regulatory T cells (Tregs). The investigators want to find out what effects, good or bad, Tregs will have on the kidney transplant patients.

There are different types of T cells. This study uses Regulatory T cells (Tregs), which are found in the blood and are part of the immune system that stops other immune cells from working. Tregs help to turn off the immune system after other immune cells have finished tackling outside infections, and Tregs keep the immune system in check so that the body does not attack itself. The researchers are hoping that, by giving an infusion of Tregs that the attack on the kidney can be stopped and kidney function will be stabilized. It is not known if the Treg experimental therapy can stop the inflammation in the kidney.

In this study, the researchers will take some of Tregs from the patient, multiply them in the laboratory, and then infuse them back into the patient. The procedure used to multiply Tregs is an experimental process performed in the laboratory. Similar procedures done with mice have been shown to reverse inflammation but it is not known whether the results will be the same in humans. This therapy has not yet been done in humans outside of a research study.

This is an open-label single dose pilot study in which 3 subjects with inflammation on their 6-month surveillance biopsy following renal transplantation will receive a single infusion of a target of 320 million cells ex vivo selected and expanded autologous polyclonal Tregs.

AAt the time of Treg infusion (day 0), the immnosuppression will remain unchanged and consists of tacrolimus and mycophenolate acid with or without steroids. On the follow up biopsy, 2 weeks after the Treg infusion, the inflammatory load will be assessed by computer assisted image analysis looking at thenumber of infiltrating cells per square mm as well as the percentage of renal cortex infiltrated with lymphocytes. If the inflammatory load has decreased by ≥50% and infused Tregs are observed in the allograft, everolimus will be started at 1.5 mg bid and the dose of tacrolimus will be decreased by 50%. After 2 weeks, tacrolimus will be discontinued. These patients will remain on everolimus and mycophenolic acid with or without prednisone through the end of the study and the follow up period. If on the 2-week follow-up biopsy, there is no decrease in the inflammatory load or there is a decrease <50%, no change will be made to the maintenance immunosuppressive regimen consisting of tacrolimus, mycophenolic acid with or without prednisone. immunosuppression. All prescribing physicians are enrolled in and will participate in the FDA Mycophenolate Risk Evaluation and Mitigation Strategy.

Subjects will be enrolled at 4-6 week intervals. The first subject will receive an infusion and will be observed for 3 weeks prior to treatment of the remaining subjects. The study team (IND sponsor, protocol chair, and medical monitor) and the members of the DSMB will review the safety data of the first subject prior to proceeding.

If no grade 3 or higher related adverse event is observed, subsequent subjects may be treated. Otherwise treatment will be suspended pending review.

Inclusion Criteria:

1. Recipients of primary renal transplants age 18-65 years with no donor specific antibodies prior to transplantation
2. Stable renal function (cGFR), no history of acute rejection and proteinuria less than 500 mg/24 hours.
3. Maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil/mycophenolic acid with or without prednisone
4. Protocol renal allograft biopsy at 6 months with findings of 5%-25% inflammation (Banff t0 or t1)without evidence of rejection (Banff t0 or t1<5%)
5. Blood PCR for BK less than 1000 copies/ml, and urine less than 500,000 copies/ml
6. History of positive EBV serology
7. Current immunizations including TdAP, hepatitis B, pneumococcal and seasonal influenza vaccines

Exclusion Criteria:

1. Recipients of 6-antigen HLA matched kidney transplants from living or deceased donors
2. Subjects with history of prior kidney transplant
3. History of transplant renal artery stenosis
4. History of wound healing complication following transplant surgery
5. Known hypersensitivity to tacrolimus, mycophenolate mofetil/mycophenolic acid, or everolimus
6. Subjects with history of autoimmune disease
7. Hematocrit < 33%; leukocytes <3,000/μL; neutrophils <1,500/μL; lymphocytes <800/μL; platelets <100,000/μL
8. Any current active infection
9. Serologic evidence of HIV-1 or HIV-2 infection
10. Evidence of current hepatitis B as demonstrated by HBsAg or circulating hepatitis B genomes
11. Serologic evidence of hepatitis C infection
12. Detectable circulating CMV genomes or active infection or high risk for CMV (CMV seronegative recipient receiving a kidney from a CMV seropositive donor)
13. Detectable circulating EBV genomes
14. History of positive PPD skin test, which was untreated.
15. Subjects who may potentially require live virus vaccines within the first 12 months of the study
16. History of malignancy (including squamous cell carcinoma of the skin or cervix) except adequately treated basal cell carcinoma
17. Any chronic illness or prior treatment which in the opinion of the investigator should preclude participation in the trial
18. Pregnant or breastfeeding women, any female who is unwilling to use a reliable and effective form of contraception for 2 years after Treg dosing, and any male who is unwilling to use a reliable and effective form of contraception for 3 months after Treg dosing
19. Tregs present in peripheral blood at less than 30/µL