Trial of Adoptive Immunotherapy With TRACT to Prevent Rejection in Living Donor Kidney Transplant Recipients

Transplantation is the treatment of choice for most causes of end stage renal disease.(1, 2)
However, without some modification of the recipient's immune system all allografts succumb
to rejection. To prevent this, patients must take immunosuppressive drugs for life,
generally a combination of steroids, a calcineurin inhibitor (CNI), such as cyclosporine or
tacrolimus, and an antiproliferative agent (azathioprine, mycophenolate mofetil or
sirolimus).(3-6) Induction with a brief course of an anti-T lymphocyte antibody preparation
(daclizumab, basiliximab, muromonab, alemtuzumab, polyclonal anti-thymocyte globulin) is
also used in approximately 70% of U.S. transplant centers.

Dependence on immunosuppression tempers the substantial benefit obtained from
transplantation (1-13). The typical regimens are relatively complex and expensive. More
importantly, they increase the risk of opportunistic infection and malignancy, and have many
non-immune side effects that hamper their tolerability. Specifically, CNIs are nephrotoxic,
a side effect of significant concern in renal transplantation. Steroids exacerbate
osteoporosis and hyperlipidemia, and cause avascular osteonecrosis. Both classes of agent
worsen glucose tolerance and hypertension, and are associated with cosmetic effects causing
non-compliance. As such, methods of transplantation that lessen the dependence on chronic
immunosuppression stand to reduce the risk and expense of transplantation. They must,
however, also prevent rejection. Development of alternate therapies that help to minimize
the need for lifelong immunosuppression, or eliminate entirely the need for drugs through
the induction of tolerance, are therefore of great interest.

Regulatory CD4+CD25+ T cells (Treg) derived from the thymus and/or peripheral tissues have
been demonstrated to broadly control T cell reactivity (14). Importantly, Tregs have been
shown to control immune responsiveness to alloantigens and significantly contribute to
operational tolerance in transplantation models (15, 16). However, there have been limited
efforts to harness the therapeutic potential of directly isolated CD4+CD25+ Treg cells for
controlling graft rejection and inducing transplantation tolerance, such as for kidney
transplants. In order for CD4+CD25+ Treg cells to be used as a clinical treatment, the
following cell properties could be necessary: ex vivo generation of sufficient numbers of
cells, migration in vivo to sites of antigenic reactivity, ability to suppress rejection in
an alloantigen-specific manner, and survival/expansion after infusion for a critical, but
currently unknown, period of time. Our published work and that of other investigators has
demonstrated 1) the feasibility of expanding Treg ex vivo, 2) the ability of these cells to
downregulate allogeneic immune responses in vitro, and 3) the efficacy of Treg for
prevention of allograft rejection in animal models (15,16). We have developed strategies for
the ex vivo expansion of naturally occurring human Tregs (nTregs) that allow for the
practical employment of this cellular therapy in the clinic. Our central hypothesis is that
sufficient human nTreg can be expanded ex vivo and used to both prevent renal transplant
rejection and facilitate the reduction and subsequent withdrawal of drug-based
immunosuppression. This study will allow for us to define the safety of Treg adoptive
cellular transfer (TRACT) in living donor renal transplant recipients that draws upon our
extensive preclinical experience with expanded Tregs, as well as our recognized clinical
expertise with designing immunosuppressive regimens compatible with this type of therapeutic
cell transfer.

Inclusion Criteria:

1. Patients who are males or females age 18-65 years.

2. Donor Age 18-65 years.

3. No prior organ transplant

4. Patients who are single-organ recipients (kidney only).

5. Women who are of childbearing potential must have a negative serum pregnancy test
before transplantation and agree to use a medically acceptable method of
contraception throughout the treatment period.

6. Subject (recipient) is able to understand the consent form and give written informed
consent.

Exclusion Criteria:

1. Known sensitivity or contraindication to sirolimus, tacrolimus or MMF.

2. Patient with significant or active infection.

3. Patients with a positive flow cytometric crossmatch using donor lymphocytes and
recipient serum.

4. Patients with PRA >20%

5. Patients with current or historic donor specific antibodies

6. Body Mass Index (BMI) of < 18 or > 35

7. Patients who are pregnant or nursing mothers.

8. Patients whose life expectancy is severely limited by diseases other than renal
disease.

9. Ongoing active substance abuse, drug or alcohol.

10. Major ongoing psychiatric illness or recent history of noncompliance.

11. Significant cardiovascular disease (e.g.):

- Significant non-correctable coronary artery disease;

- Ejection fraction below 30%;

- History of recent myocardial infarction.

12. Malignancy within 3 years, excluding nonmelanoma skin cancers.

13. Serologic evidence of infection with HIV or HBVsAg positive.

14. Patients with a screening/baseline total white blood cell count < 4,000/mm3; platelet
count < 100,000/mm3; triglyceride > 400 mg/dl; total cholesterol > 300 mg/dl.

15. Investigational drug within 30 days prior to transplant surgery.

16. Anti-T cell therapy within 30 days prior to transplant surgery.