Treg Adoptive Therapy for Subclinical Inflammation in Kidney Transplantation

NCT02088931 | Completed Phase 1 DMC

• 1 other identifier: UCSFTX412ST
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Late Complication From Kidney Transplant

Keywords

Tregs; Kidney transplantation

Outcome Measures

Primary Outcomes (4)

• 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

• Patient Survival

  Patient survival at 1 year and 3 years post renal transplantation.

  3 years

• Renal Allograft Survival

  Renal allograft survival at 1 year and 3 years post renal transplantation.

  3 years

• Renal Allograft Dysfunction

  Incidence of renal allograft dysfunction during the 1 year follow-up period post Treg infusion.

  1 year

Secondary Outcomes (2)

• Presence of Intragraft Tregs in the Renal Allograft Biopsy

  2 weeks

• Change in circulating Treg Cells

  2 weeks

Other Outcomes (1)

• Change from Baseline in Urinary Protein

  1 year

Study Arms (1)

Single infusion polyclonal Treg

EXPERIMENTAL

3 subjects with inflammation on their 6-month surveillance biopsy following renal transplantation will receive a single infusion of a target of 320 million ex vivo selected and expanded autologous polyclonal Tregs. After the therapy visit the patient will return for a total of nine (9) more visits for the main part of the study: 1 and 4 days after therapy, then once a week for 4 weeks, and then 3, 6, and 12 months after you get the therapy.

Biological: Treg infusion

Interventions

Treg infusion BIOLOGICAL

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.

Single infusion polyclonal Treg

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Recipients of primary renal transplants age 18-65 years with no donor specific antibodies prior to transplantation
• Stable renal function (cGFR), no history of acute rejection and proteinuria less than 500 mg/24 hours.
• Maintenance immunosuppression consisting of tacrolimus and mycophenolate mofetil/mycophenolic acid with or without prednisone
• 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%)
• Blood PCR for BK less than 1000 copies/ml, and urine less than 500,000 copies/ml
• History of positive EBV serology
• Current immunizations including TdAP, hepatitis B, pneumococcal and seasonal influenza vaccines

You may not qualify if:

• Recipients of 6-antigen HLA matched kidney transplants from living or deceased donors
• Subjects with history of prior kidney transplant
• History of transplant renal artery stenosis
• History of wound healing complication following transplant surgery
• Known hypersensitivity to tacrolimus, mycophenolate mofetil/mycophenolic acid, or everolimus
• Subjects with history of autoimmune disease
• Hematocrit \< 33%; leukocytes \<3,000/μL; neutrophils \<1,500/μL; lymphocytes \<800/μL; platelets \<100,000/μL
• Any current active infection
• Serologic evidence of HIV-1 or HIV-2 infection
• Evidence of current hepatitis B as demonstrated by HBsAg or circulating hepatitis B genomes
• Serologic evidence of hepatitis C infection
• Detectable circulating CMV genomes or active infection or high risk for CMV (CMV seronegative recipient receiving a kidney from a CMV seropositive donor)
• Detectable circulating EBV genomes
• History of positive PPD skin test, which was untreated.
• Subjects who may potentially require live virus vaccines within the first 12 months of the study

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (4)

• 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. doi: 10.1097/01.tp.0000128167.60172.cc.

  PMID: 15280685 RESULT

• 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. doi: 10.1097/01.tp.0000225783.86950.c2.

  PMID: 16861939 RESULT

• 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.

  PMID: 18510923 RESULT

• 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.

  PMID: 22170955 RESULT

Study Officials

• Flavio Vincenti, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2014
• First Posted: March 17, 2014
• Study Start: March 1, 2014
• Primary Completion: December 31, 2016
• Study Completion: December 31, 2016
• Last Updated: July 13, 2022

Record last verified: 2022-07

Locations

US (1)