REgulatory T Cell Therapy to Achieve Immunosuppression REduction

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)

Inclusion criteria

All inclusion criteria must be met prior to randomization.

• Males or females aged 18-65 years as of the date of informed consent who will undergo a single organ, living donor kidney transplant.
• 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.
• 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.

• No prior organ transplant of any kind.
• 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.
• 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.
• Subjects (recipients) must be able to understand the consent form and give written informed consent prior to any trial procedure.
• 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 collections.

Exclusion criteria

Based on SOC Pre-Transplant Evaluation

The following exclusion criteria must be determined prior to randomization per SOC pre-transplant evaluation.

• Known sensitivity or contraindication to thymoglobulin, everolimus, sirolimus, or tacrolimus or other immunosuppression medication prescribed.
• Subjects with a positive crossmatch by virtual cross matching or complement-dependent cytotoxicity (CDC) cross matching or flow cytometry cross matching (FCXM).
• 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.
• Subjects with current or historic donor specific antibodies.
• Body Mass Index (BMI) of < 16 kg/m2 or > 38 kg/m2 per SOC pre-transplant evaluation.
• Subjects who are pregnant or nursing mothers.
• Subjects whose life expectancy is severely limited by diseases other than renal disease, per judgement of an investigator.
• Ongoing active drug or alcohol substance abuse, per judgement of an investigator.
• Major ongoing psychiatric illness or recent history of noncompliance with current medical therapy, per judgement of an investigator.
• 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.
• Subjects who require use of chronic anticoagulation medications. Use of anti-platelet medications will be allowed in absence of a documented arrhythmia.
• Malignancy within 3 years, excluding non-melanoma skin cancers such as basal cell carcinoma and squamous cell carcinoma.
• Serologic evidence of active infection with HCV, HIV or HBV per SOC pre-transplant evaluation. Historical data within three months of transplant are acceptable.
• 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, activated partial thromboplastin time <21.6 or > 42.3 seconds, fibrinogen <177 mg/dL or >598 mg/dL, and INR <0.64 or >1.4.
• Subjects with underlying renal disease etiologies with high risk of disease recurrence such as primary focal segmental glomerulosclerosis and others per investigator discretion.
• 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.
• Diabetic subjects with an HbA1c of >8%.

The following exclusion criteria must be determined prior to transplant per SOC pre-transplant evaluation.

• Subjects with an active infection considered clinically significant by an investigator that has not resolved prior to transplant.

Exclusion criteria

Prior to Leukapheresis (Arm 2)

• Subjects with an active infection considered clinically significant by an investigator that has not resolved prior to leukapheresis.
• 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).
• Subjects who are pregnant or nursing.
• Subjects who received an investigational drug within 30 days prior to leukapheresis.
• Subjects who received anti-T cell therapy within 30 days prior to leukapheresis.
• 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)

• Subjects with an active infection considered clinically significant by the investigator that has not resolved prior to planned Treg infusion.
• Subjects with a new, clinically significant medical condition that, per investigator opinion, would impact the ability to safely administer TRK-001.
• Subjects who experience a rejection episode of the kidney graft prior to the planned Treg infusion.
• 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.
• Subjects who received an investigational drug within 30 days prior to infusion.
• Subjects who received anti-T cell therapy within 30 days prior to infusion.