REgulatory T Cell Therapy to Achieve Immunosuppression REduction

The goal of this multi-national, multi-center, open-label, randomized Phase 2 trial is to determine the safety and efficacy of administering expanded regulatory T cells (TRK-001) to prevent allograft rejection in living donor renal transplant recipients.

Enrolled subjects will be randomized to one of 2 study arms:

Arm 1 subjects will receive standard of care immunosuppression

Arm 2 subjects will receive initial standard of care (SOC) immunosuppression and a single infusion of TRK-001. Three months after the transplant, Arm 2 subjects may be able to begin reducing their immunosuppression medication to a 1-drug regimen.

The primary outcome measures of trial are to evaluate several components indicating immunologic problems with the transplanted organ at 1-year post-transplant and to evaluate the ability for the study subjects given TRK-001 to wean to a 1-drug immunosuppression regimen.

All enrolled subjects will be followed for 5 years post-transplant.

This is a prospective, multi-national, multi-center, open-label, randomized Phase 2 trial to determine the safety and efficacy of administering autologous expanded regulatory T cells (TRK-001) to prevent allograft rejection in living donor renal transplant recipients.

All subjects will be followed for 5 years post-transplant, comprising of a 2-year post-transplant follow-up period and a 3-year surveillance period.

Subjects with end-stage renal disease undergoing a living donor kidney transplant will be enrolled into the trial as follows:

Arm 1 SOC: Standard of care immunosuppression (N=14)

Arm 2 TRACT/MONO: TRK-001 and initial SOC immunosuppression weaned to monotherapy (N=20)

At Month 3 post-transplant, Arm 2 subjects will be further randomized prior to weaning to either mTOR or CNI monotherapy as follows:

Arm 2A: TRACT/MONO mTOR (N=10) or Arm 2B: TRACT/MONO CNI (N=10)

Eligibility Criteria:
Inclusion Criteria

1. Males or females aged 18-65 years as of the date of informed consent who will undergo a single organ, living donor kidney transplant.
2. Donor aged 18-65 years as of the date of organ donation. A certain degree of HLA matching between the donor and the recipient is not required.
3. Blood type compatibility between recipient and donor must be established as follows.

   Recipient A to Donor A or O; Recipient B to Donor B or O; Recipient AB to Donor A, B, AB, or O; Recipient O to Donor O.
4. No prior organ transplant of any kind.
5. Women of childbearing potential must agree to use a medically acceptable method of contraception throughout the trial. A list of the medically acceptable methods of contraception are listed in the informed consent document.
6. Male patients must agree to use birth control following the initiation of standard-of-care immunosuppression and for a minimum of 6 months following kidney transplant.
7. Subjects (recipient) must be able to understand the consent form and give written informed consent prior to any trial procedure.
8. If donor informed consent is required by IRB/IEC, donor must be able to understand the consent form and give written informed consent prior to any trial procedure. Note: Donor informed consent is required for donors participating in the research assay collection (anti-donor ELISPOT).

Exclusion Criteria Based on SOC Pre-Transplant Evaluation

1. Known sensitivity or contraindication to thymoglobulin, everolimus, sirolimus, or tacrolimus or other immunosuppression medication prescribed.
2. Subjects with an active infection considered clinically significant by an investigator that has not resolved prior to transplant.
3. Subjects with a positive flow cytometric crossmatch using donor lymphocytes and recipient serum.
4. Subjects with PRA \>80% per SOC pre-transplant assessment. PRA must be repeated prior to transplant if patient receives a blood product transfusion after the initial assessment.
5. Subjects with current or historic donor specific antibodies.
6. Body Mass Index (BMI) of \< 16 kg/m2 or \> 38 kg/m2 per SOC pre-transplant evaluation.
7. Subjects who are pregnant or nursing mothers.
8. Subjects whose life expectancy is severely limited by diseases other than renal disease, per judgement of an investigator.
9. Ongoing active drug or alcohol substance abuse, per judgement of an investigator.
10. Major ongoing psychiatric illness or recent history of noncompliance with current medical therapy, per judgement of an investigator.
11. Significant cardiovascular disease (e.g.):

    * Significant non-correctable coronary artery disease, per judgement of an investigator
    * Ejection fraction below 30% per SOC echocardiogram if an echocardiogram is performed for an individual subject as part of their pre-transplant evaluation
    * History of recent (\< 12 months) myocardial infarction at time of informed consent
    * History of recent (within 3 months) vascular intervention(s) for coronary artery disease at the time of informed consent
    * Documented arrhythmias that require a pacemaker or medical therapy for control.
12. Subjects who require use of chronic anticoagulation medications. Use of anti-platelet medications will be allowed in absence of a documented arrhythmia.
13. Malignancy within 3 years, excluding non-melanoma skin cancers such as basal cell carcinoma and squamous cell carcinoma.
14. Serologic evidence of infection with HCV, HIV or HBVsAg positive per SOC pre-transplant evaluation.
15. Subjects with a total white blood cell count \< 4,000/mm3; platelet count \< 50,000/mm3; triglyceride \> 400 mg/dL; total cholesterol \> 300 mg/dL, prothrombin time \<8.4 seconds or \>15.7 seconds, partial thromboplastin time \<20.2 seconds or \>45.7 seconds, fibrinogen \<177 mg/dL or \>598 mg/dL, and INR \<0.64 or \>1.4.
16. Subjects with underlying renal disease etiologies with high risk of disease recurrence such as primary focal segmental glomerulosclerosis and others per investigator discretion.
17. Subjects requiring the use of chronic immunosuppressive medication to control an underlying renal disease, or a disease with extrarenal manifestations (i.e., inflammatory bowel disease). Subjects requiring chronic or intermittent use of inhaled corticosteroids for respiratory conditions will be allowed.
18. Diabetic subjects with an HbA1c of \>8%.

Exclusion Criteria Prior to Leukapheresis

1. Subjects with an active infection considered clinically significant by an investigator that has not resolved prior to leukapheresis.
2. Subjects with PRA \>80%, if repeated after SOC pre-transplant assessment. (PRA must be repeated prior to leukapheresis if patient receives a blood product transfusion after the initial assessment).
3. Subjects who are pregnant or nursing.
4. Subjects who received an investigational drug within 30 days prior to leukapheresis.
5. Subjects who received anti-T cell therapy within 30 days prior to leukapheresis.
6. Subjects who do not meet pre-leukapheresis clearance parameters per institutional practices or per investigator discretion.

Exclusion Criteria Prior to TRACT Cellular Product Infusion (Arm 2)

1. Subjects with an active infection considered clinically significant by the investigator that has not resolved prior to planned Treg infusion.
2. Subjects with a new, clinically significant medical condition that, per investigator opinion, would impact the ability to safely administer TRK-001.
3. Subjects who experience a rejection episode of the kidney graft prior to the planned Treg infusion.
4. Subjects who are pregnant or nursing. Women who are of childbearing potential must have a negative urine or serum pregnancy test before infusion of TRK-001.
5. Subjects who received an investigational drug within 30 days prior to infusion.
6. Subjects who received anti-T cell therapy within 30 days prior to infusion.