Tolerance by Engaging Antigen During Cellular Homeostasis

Background:The most common problem following a kidney transplant is the development of acute
or chronic rejection. Rejection is the immunologic reaction in which the body refuses to
accept the transplanted organ. The body's immune system will make destructive antibodies that
will attempt to attack the transplanted organ.

In order to prevent organ rejection, all patients receiving an allograft (a graft
transplanted between genetically non-identical individuals of the same species) must take
anti-rejection (immunosuppressive) therapy. These medications function by lowering the body's
natural immune system. Often these medications are associated with significant side effects
ranging from infections to cancer.

Study:

This is a single center, open label, dose-escalation clinical trial in 6 adult recipients of
Human Leukocyte Antigen (HLA)- non-identical, living-donor renal allografts. All participants
will receive induction therapy with alemtuzumab followed by maintenance therapy with
sirolimus and belatacept.

A total of 3 dosing cohorts of 2 recipients each will receive 12 infusions of donor-derived
MSCs starting on Day 42 post-transplant and every 4 weeks starting on Day 56 post-transplant,
with a minimum of 7 days between the first and second MSC infusions.

The primary objective is to determine whether immune reconstitution after lymphocyte
depletion in the setting of co-stimulatory blockade and systemic MSC-derived donor antigen
can promote operational tolerance in recipients of kidney allografts.

Participants will be evaluated for eligibility for sirolimus withdrawal any time between week
52 and week 104 post-transplant. Participants who successfully complete sirolimus withdrawal
will remain on belatacept monotherapy for at least 24 weeks before being assessed for
eligibility to discontinue belatacept. Participants who successfully complete
Immunosuppression Withdrawal (ISW) will then undergo 24 weeks of high frequency follow up
followed by 132 weeks of standard follow up.

Study participation may continue for up to seven (7) years after kidney transplant surgery.

*** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the
Immune Tolerance Network do not recommend the discontinuation of immunosuppressive therapy
for recipients of cell, organ, or tissue transplants outside of physician-directed,
controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can
result in serious health consequences and should only be performed in certain rare
circumstances, upon the recommendation and with the guidance of your health care provider.

Inclusion Criteria:

Recipient:

- Adult candidates of an human leukocyte antigen (HLA)-non-identical, living-donor
kidney transplant:

--Candidates must meet the United Network for Organ Sharing (UNOS) criteria, including
laboratory criteria, for transplant listing;

- Serologic evidence of prior Epstein-Barr Virus (EBV) infection, as documented by
positive IgG and negative IgM antibodies against EBV;

- Serological evidence of prior Cytomegalovirus (CMV) infection if donor is CMV
positive;

- For women of child bearing potential:

- A negative serum or urine pregnancy test with sensitivity of less than 50 mIU/mL
within 72 hours of start of study medication; and

- Agreement to use contraception:

--- According to the FDA Office of Women's Health
(http://www.fda.gov/birthcontrol), there are a number of birth control methods
that are more than 80% effective

----Female recipients of child-bearing potential must consult with their
physician and determine the most suitable method(s) from this list to be used for
18 months after the first dose of study therapy.

Donor:

- Meets institutional selection criteria for organ and bone marrow donation:

--All donors will be screened and tested in accordance with:

- (i) FDA 21 CRF 1271.85 requirements for donors of human cells, tissues, and
cellular- and tissue-based products (HCT/P); and

- (ii) standards for living kidney donors testing for infection established by the
United Network for Organ Sharing (UNOS).

- Ability to understand and provide informed consent for all study procedures including
kidney transplant and bone marrow harvest.

Exclusion Criteria:

Recipient:

- History of any immunodeficiency syndrome (including Human Immunodeficiency Virus-1
(HIV-1) and HIV-2);

- Positive anti-Hepatitis C Virus (HCV) Polymerase Chain Reaction (PCR), anti-Hepatitis
C Virus (HBV) PCR, or HBV surface antigen;

- History of malignancy within 5 years of enrollment or any history of hematogenous
malignancy or lymphoma; --Exception: Participants with curatively treated
non-melanomatous skin cancer or curatively treated cervical carcinoma in situ may be
enrolled.

- Underlying renal disease with high likelihood of recurrence, including but not limited
to:

- primary focal segmental glomerulosclerosis (FSGS),

- Type I or II membranoproliferative glomerulonephritis (MPGN),

- hemolytic-uremic syndrome and

- thrombotic thrombocytopenic purpura (HUS/TTP) syndrome. ---Subject(s) with
end-stage renal disease (ESRD) of unknown etiology and/or has no histologically
confirmed diagnosis, may be enrolled into the study as long as there are no
clinical signs or symptoms consistent with excluded clinical diagnoses.

- History of active M. tuberculosis:

--Participants with a history of latent M. tuberculosis (LTB) as defined by positive
testing for tuberculosis using an approved IGRA blood test, such as QuantiFERON®-Gold
TB or T-SPOT-TB assay must:

- have completed treatment for LTB and

- have a negative chest x-ray. ----All participants will undergo IGRA testing for M
tuberculosis within 3 months prior to transplant.

- Current or historical evidence of donor-specific antibody;

- Immunosuppressive drug therapy within one year prior to enrollment.

- May not be taking or have taken prednisone, cyclosporine A, tacrolimus, azathioprine,
Mycophenolate Mofetil (MMF), cyclophosphamide, methotrexate, infliximab, etanercept,
or other agents which have a primary therapeutic effect of immunosuppression in the
year prior to transplantation.

- May not have taken depletional anti-lymphocyte agents at any time.

---Exceptions:

- Short (≤ 30 days) courses of topical or inhaled steroids are permitted, as are

- Short oral or parental pulses for a documented hypersensitivity reaction.

- Active autoimmune disease requiring ongoing immunosuppressive therapy or other
conditions in which there is an anticipated need for immunosuppressive maintenance
therapy;

- Uncompensated congestive heart failure or pulmonary edema;

- Active severe infection within a month of the screening visit;

- Use of an investigational drug within 30 days of the screening visit;

- Presence of any medical condition that the investigator deems incompatible with trial
participation; or

- Inability or unwillingness to comply with protocol monitoring and therapy.

Donor:

- History of blood donation to the recipient;

- Evidence of prior Cytomegalovirus (CMV) infection if the recipient is CMV negative;

- History of HIV-1/HIV-2 infection;

- Positive HCV PCR, HBV PCR or HBV surface antigen;or

- Presence of any medical condition that the investigator deems incompatible with trial
participation.