Bone Marrow Stromal Cell Infusions for Stem Cell Transplant Complications

Bone marrow stromal cells (BMSC) derived from bone marrow aspiration/biopsy have important
anti-inflammatory and immunosuppressive properties that make them suitable candidates for
cellular therapy of inflammatory and degenerative disorders. BMSC suppress lymphocyte immune
responsiveness and can hone in to sites of inflammation and promote healing. BMSC were first
used in man to successfully treat refractory acute graft versus host disease (aGVHD). A
recent multicenter study treating refractory aGVHD reported a 66% response rate and a
sustained survival in responding patients. BMSC are currently being evaluated in acute GVHD
in several ongoing studies worldwide. BMSC have also been used to treat post-transplant
conditions not directly due to GVHD. Responses have been reported in hemorrhagic cystitis,
and pneumoperitoneum. BMSC are also under evaluation in the treatment of inflammatory and
autoimmune disorders.

The Cell Processing Section of the Department of Transfusion Medicine at the Clinical Center
NIH has developed a procedure for collecting, expanding and cryopreserving clinical grade
BMSC under an FDA Drug Master File (DMF). Marrow will be aspirated from volunteer donors
participating on protocol 10-CC-0053 who have passed the standard screening for blood and
marrow donors and BMSC will be expanded in vitro. Since it is not necessary to HLA-match BMSC
donors with their recipient for this study, a BMSC repository will be used as the source of
BMSC for this study.

This will be the first trial of the safety of the NIH BMSC cellular product in stem cell
transplant recipients. In this phase I study, open to adult NIH allogeneic stem cell
transplantation (SCT) recipients, we will evaluate the safety of a fixed dose of BMSC
infusions (target dose of 2 x 106 BMSCs /kg (+/- 10%)) in patients with acute GVHD, marrow
failure or tissue injury following allogeneic SCT. Up to three BMSC infusions will be given
every 7 3 days apart. Safety will be monitored continuously with a stopping rule for toxicity
based on the treatment-related serious adverse event rate. Organ-specific clinical responses
will be measured. Where possible we will also attempt to identify transfused BMSC in sites of
damage in biopsy material. It is planned to accrue up to 10 subjects over a 6-month period.

- INCLUSION CRITERIA:

5.1.1 History of allogeneic SCT

Any subject who has received an allogeneic SCT at NIH is eligible if they have one or more
of the following conditions. Subjects may continue to receive standard treatments for their
condition but may not be entered onto a new investigational protocol to treat the condition
during the period of evaluation of BMSC infusions.

5.1.1.1 Acute GVHD

Biopsy confirmed within 14 days of investigational intervention (unless not possible to
perform because of anatomical location or clinical contraindication) acute GVHD affecting
gut and/or liver and/or skin, defined as steroid refractory: failure to respond to greater
than or equal to 2mg/kg methylprednisolone (or equivalent) after 7 days OR steroid
dependent: requiring methylprednisolone (or equivalent) greater than or equal to 1mg/kg for
greater than or equal to 7days for control of GVHD. GVHD affecting the skin alone is rarely
lethal and is excluded. Acute GVHD is defined using the NIH consensus definition inclusive
of Classic acute (< 100 days after transplant or DLI, presence of acute GVHD features,
absence of chronic GVHD features) AND Persistent/recurrent/late onset acute (> 100 days
after transplant or DLI, presence of acute GVHD features, absence of chronic GVHD
features).

5.1.1.2 Marrow Failure

Poor graft function in the presence of >95% donor myeloid chimerism: defined as platelet or
red cell transfusion dependent OR absolute neutrophil count persisting <500/ (Micro)l for
14 days without other reversible or treatable causes.

5.1.1.3 Pulmonary injury

Lung injury from: Diffuse alveolar hemorrhage (DAH), Cryptogenic Organizing Pneumonia
(COP), Bronchiolitis Obliterans Syndrome (BOS), idiopathic interstitial pneumonia (IP),
Adult respiratory distress syndrome (ARDS) diagnosed by exclusion of active infection. Also
worsening pneumomediastinum or pneumothorax persisting after 7 days; at risk for causing
hemodynamic changes in association with any of these diagnoses.

5.1.1.4 Hepatic injury

Clinically diagnosed sinusoidal obstruction syndrome (SOS), previously known as
veno-occlusive disease (VOD), with bilirubin > 2 times ULN or transaminases >3 times ULN
and rising.

5.1.1.5 Hemorrhagic cystitis (HC)

HC requiring continuous bladder irrigation OR requiring red cell or platelet transfusions
at least intermittently for the past 7 days OR HC unresponsive to antivirals after 10 days.

5.1.1.6 Gastrointestinal tract

Pneumoperitoneum, bowel perforation not susceptible to corrective surgery OR blood
transfusion requirement > 1 unit per day for 7 days.

5.1.2 Age: greater than or equal to 18 years of age and less than or equal to 75 years of
age.

5.1.3 Birth Control

Subjects of childbearing or child-fathering potential must be willing to use a medically
acceptable form of birth control, which includes abstinence, while they are being treated
on this study.

5.1.4 Transplant performed at NIH.

EXCLUSION CRITERIA:

5.2.1 Breast feeding or pregnant females (due to unknown risk to fetus or newborn).

5.2.2 Allergic to gentamicin

5.2.3 Weight less than 20 kg (not informative for research sampling)

5.2.4 Patients with significant organ failure at baseline as evidenced by any of the
following:

1. Symptomatic cardiac failure at rest or with minimal activity or exertion for
which intervention is indicated

2. Creatinine > 3.0 X ULN

3. Decreased oxygen saturation at rest (e.g. pulse oximeter < 88% or PaO2 less than
or equal to 55 mmHg)