Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Renal Transplantation (The ONE Study )

This Phase I pilot study will evaluate the safety, and tolerability of darTreg infusion for adult, de novo, living donor renal transplant recipients.

A single-center, open-label, dose-escalation pilot trial of a single infusion of darTregs in two dosing cohorts. This study is an independent single-center clinical trial. However, the organizational and mechanistic infrastructure of the study will be provided by the ONE Study project, a European Union funded collaborative project, whose objective is to assess distinct purified hematopoietic immunoregulatory cells as clinical therapies in solid organ transplantation. This study is one of multiple clinical trials within the framework of The ONE Study project, based on the same general design.

Eligibility Criteria:
Inclusion Criteria: (organ donor eligibility)

1. Eligible for live kidney donation
2. At least 18 years of age
3. An ABO blood type compatible with the organ recipient
4. Willing and able to provide a blood sample for The ONE Study IM (Immune Monitoring) Subproject
5. Willing to provide personal and medical/biological data for the trial analysis
6. Eligible to give blood for B cell source prior to organ donation
7. Signed and dated written informed consent\*. \*For subjects unable to read and/or write, oral informed consent observed by an independent witness is acceptable if the subject has fully understood oral information given by the Investigator. The witness should sign the consent form on behalf of the subject.

In signing the donor information sheet/informed consent form (DIS/ICF), organ donors agree to undergo phlebotomy to provide donor B cells for the production of darTreg, to provide a blood sample for the IM Subproject, and permit access to their medical records for the collection of specified demographic and medical/biological data for the trial.

Organ Recipient eligibility:

A prospective kidney transplant recipient is eligible for enrollment into the study if all of the following inclusion criteria apply:

1. Chronic renal insufficiency necessitating kidney transplantation and approved to receive a primary kidney allograft from a living donor
2. At least 18 years of age
3. Able to commence the immunosuppressive regimen at the protocol-specified time point
4. Willing and able to participate in The ONE Study IM and HEC (Health-Economics Subproject) subprojects
5. Adequate venous access to support leukapheresis
6. Signed and dated written informed consent\*.

   * For patients unable to read and/or write, oral informed consent observed by an independent witness is acceptable if the patient has fully understood oral information given by the Investigator. The witness should sign the consent form on behalf of the patient.

Exclusion Criteria: (organ donor)

If a prospective donor fulfills any of the following criteria, they are ineligible for the trial:

1. Genetically identical to the prospective organ recipient at the HLA (human leukocyte antigen) loci (0-0-0 mismatch)
2. CMV-positive and donating to a CMV-negative recipient
3. Exposure to any investigational agents at the time of kidney donation, or within 28 days prior to kidney donation
4. Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator and/or designated study personnel
5. Subjects unable to freely give their informed consent (e.g. individuals under legal guardianship).

Exclusion criteria (organ recipient)

1. Patient has previously received any tissue or organ transplant other than the planned kidney graft
2. Known contraindication to the protocol-specified treatments / medications
3. Genetically identical to the prospective organ donor at the HLA (human leukocyte antigen) loci (0-0-0 mismatch)
4. PRA (panel reactive antibody) grade \> 40% within 6 months prior to enrollment
5. Previous treatment with any desensitization procedure (with or without IVIg)
6. Concomitant malignancy or history of malignancy within 5 years prior to planned study entry (excluding successfully-treated non-metastatic basal/squamous cell carcinoma of the skin)
7. Evidence of significant local or systemic infection
8. HIV-positive, EBV-negative or suffering chronic viral hepatitis
9. CMV-negative and receiving a kidney from a CMV-positive donor
10. Significant liver disease, defined as persistently elevated AST (aspartate aminotransferase) and/or ALT(alanine aminotransferase) levels \> 2 x ULN (Upper Limit of Normal range)
11. Malignant or pre-malignant hematological conditions
12. Neutrophils \< 1000/μl ; platelets \< 100,000/μl
13. Regulatory T cells present in peripheral blood at \<30/µL
14. Any uncontrolled medical condition or concurrent disease that could interfere with the study objectives
15. Any condition which, in the judgment of the Investigator, would place the subject at undue risk
16. Ongoing treatment with systemic immunosuppressive drugs at study entry
17. Patients who have received anti-T cell therapy within 30 days prior to transplant surgery
18. Participation in another clinical trial during the study or within 28 days prior to planned study entry
19. Female patients of reproductive potential with a positive pregnancy test at enrollment
20. Female patients who are breast-feeding
21. All female patients of reproductive potential\* UNLESS the patient is willing to use an acceptable birth control for the duration of the study unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely) (See Table 2. Acceptable Contraception Methods for Females of Reproductive Potential)
22. Male patients unwilling to use a reliable and effective form of contraception for 3 months after darTreg dosing
23. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule
24. Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator and/or designated study personnel
25. Patients unable to freely give their informed consent (e.g. individuals under legal guardianship).

    * Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility. Menopause should be clinically confirmed by a patient's healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy) or 2) postsurgical from a bilateral oophorectomy.

Exclusion Criteria B (organ recipient)

Below are exclusion criteria to be assessed post-transplantation and prior to darTreg infusion. Subjects who meet any of these criteria should not receive a darTreg-infusion:

1. Unacceptable darTreg product.
2. Delayed graft function (requiring dialysis post-transplant).
3. Requiring oxygen supplementation to keep capillary oxygen saturations \>95%.
4. Any medical or technical complications (e.g. myocardial infarction, urine leak, wound dehiscence, pneumonia, ongoing fevers, etc.) that in the judgment of the investigators or responsible clinician would put the subject at undue risk.-