Treg Adoptive Therapy for Subclinical Inflammation in Kidney Transplantation

Late Complication From Kidney Transplant Clinical Trial

— TASK  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02088931
• Other study ID #: UCSFTX412ST
• Status: Completed
• Phase: Phase 1
• Start date: March 2014
• Est. completion date: December 31, 2016

Study information

• Verified date: July 2022
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: December 31, 2016
• Est. primary completion date: December 31, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Late Complication From Kidney Transplant

Intervention

Biological:
• Treg infusion
At the time of Treg infusion (day 0), maintenance immunosuppression will remain unchanged which consists of TAC, MPA and steroids. On follow-up biopsy 2 weeks after Treg infusion, the inflammatory load will be assessed by computer assisted image analysis looking at the number 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, mycophenolic acid and 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 TAC, MPA and prednisone.

Locations

Country	Name	City	State
United States	University of California, San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Francisco

Country where clinical trial is conducted

United States, 

References & Publications (4)

Kee TY, Chapman JR, O'Connell PJ, Fung CL, Allen RD, Kable K, Vitalone MJ, Nankivell BJ. Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants. Transplantation. 2006 Jul 15;82(1):36-42. — View Citation

Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. Natural history, risk factors, and impact of subclinical rejection in kidney transplantation. Transplantation. 2004 Jul 27;78(2):242-9. — View Citation

Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008 May 30;133(5):775-87. doi: 10.1016/j.cell.2008.05.009. Review. — View Citation

Tang Q, Bluestone JA, Kang SM. CD4(+)Foxp3(+) regulatory T cell therapy in transplantation. J Mol Cell Biol. 2012 Feb;4(1):11-21. doi: 10.1093/jmcb/mjr047. Epub 2011 Dec 14. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change from Baseline in Urinary Protein	Assess surrogate markers of immune response by measuring changes in urinary protein and reflecting immune infiltration, inflammation, and tubular injury. (composite measure)	1 year
Primary	Number of Patients with Adverse Events.	Participants will be assessed for adverse events on days 0-1 (Treg infusion) and on days 4,7,14,21,28,84,180, and 360 (1 year).	1 year
Primary	Patient Survival	Patient survival at 1 year and 3 years post renal transplantation.	3 years
Primary	Renal Allograft Survival	Renal allograft survival at 1 year and 3 years post renal transplantation.	3 years
Primary	Renal Allograft Dysfunction	Incidence of renal allograft dysfunction during the 1 year follow-up period post Treg infusion.	1 year
Secondary	Presence of Intragraft Tregs in the Renal Allograft Biopsy	Treg infiltration will be measured in the renal allograft on the post infusion kidney biopsy to observe the persistence of deuterium-labeled Tregs within the allograft.	2 weeks
Secondary	Change in circulating Treg Cells	Percentage of circulating Treg cells detected using deuterium labeling in the allograft biopsy.	2 weeks