Early Treatment of Acute Graft Versus Host Disease With Bone Marrow-Derived Mesenchymal Stem Cells and Corticosteroids

This is a pilot study evaluating the addition of bone marrow-derived mesenchymal stem cell
(BMSC) infusions to corticosteroids for the early treatment of acute graft versus host
disease (GVHD). Acute GVHD is a major complication following allogeneic stem cell transplant.
GVHD occurs when T-lymphocytes in the donor graft respond to signals from recipient cells and
cause tissue damage. This process can lead to organ injury, increased risk of infection, and
graft failure. Corticosteroids have been used as the primary therapy for acute GVHD for
decades, and guidelines currently recommend their use as front line treatment. Recent
prospective data from the Blood and Marrow Transplant Clinical Trials Network shows that GVHD
will be cured in about half of patients with steroids alone. Patients who do not respond to
steroids are considered steroid-resistant, and this is associated with much worse survival.
It is possible to predict which patients will go on to have steroid-resistant GVHD by
measuring the plasma concentration of the molecule called suppression of tumorigenicity 2
(ST2). BMSC infusions have been used to treat steroid-resistant acute GVHD successfully, but
despite a track record of safety, little is known about the use of BMSC in the early
treatment setting. The main objective of this study is to explore the feasibility of
administering BMSC within 5 days of diagnosis of acute GVHD. Our study will for the first
time use the ST2 biomarker to more accurately assign acute GVHD to steroid refractory or
sensitive, and explore changes in ST2 and other biological markers of BMSC function and their
correlation with clinical response. In the process of this study, we will assess the safety
and feasibility of early treatment according to our regimen, obtain estimates of efficacy at
important GVHD therapy time points, and determine if treatment with BMSC can prevent the
progression of GVHD in patients with high risk of GVHD progression as measured by biomarkers.

The Cell Processing Section of the Department of Transfusion Medicine at the Clinical Center
NIH has developed a BMSC repository at NIH. The NIH BMSC are a third party, early passage
product based on the EU manufacturing approach. The NIH BMSC cellular product was
administered safely to transplant recipients with steroid-resistant acute GVHD in a phase I
study (protocol 12-H-0010, IND #14596) conducted from March 2012 to October 2012 at NIH. This
pilot study is a continuation of the previous study and open to allogeneic stem cell
transplantation recipients at NIH (age greater than or equal to 4 yrs) with de novo acute
GVHD requiring systemic therapy either directly after allogeneic transplantation or following
treatment with donor lymphocyte infusion. Subjects will receive BMSC infusions (target dose
of 2 times 10(6) BMSC/kg for up to 12 doses) in addition to standard upfront therapy with
corticosteroids. The primary endpoint will be the proportion of patients without a
treatment-related severe adverse event (TRSAE) at day +56. Responses will be assessed at day
+28 and +56 from the initial diagnosis. Responses will be correlated to changes in GVHD
biomarkers including ST2, Reg3a, TNFR1, and IL-6. Subjects will be enrolled at first
diagnosis of acute GVHD, and the first BMSC infusion will be given within 120 hours of the
first dose of corticosteroids. BMSC infusions will be given twice weekly for the first 4
weeks. Subjects with a complete response at the end of week 4 will not receive further
infusions. All other subjects will receive BMSC infusions weekly for four additional weeks.
Safety will be monitored continuously with a stopping rule for toxicity based on the
treatment-related serious adverse event rate. Research samples will be drawn at regular
intervals to explore biological correlates of response and to investigate the mechanism of
action of BMSC.

- INCLUSION CRITERIA:

- History of any grade acute GVHD requiring systemic therapy after allogeneic stem cell
transplant or DLI.

--Subjects must have received an allogeneic stem cell transplant at NIH and be
diagnosed with acute GVHD. Acute GVHD is defined using the NIH consensus definition
inclusive of classic acute (less than or equal to 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). Subjects with stage I and II
skin only (overall Grade I) or isolated upper gastrointestinal involvement are
eligible if the treating physician deems that systemic corticosteroid treatment is
indicated. Biopsy confirmation of GVHD is desirable, but not required for study entry
because enrollment should not be delayed awaiting biopsy or pathology results.
Patients must be diagnosed with a first episode of acute GVHD requiring systemic
corticosteroids and associated with preceding administration of a cellular therapy
including stem cells and donor lymphocyte infusion. Patients who were treated for GVHD
associated with another cellular therapy product (e.g. prior allogeneic transplant or
DLI) will be allowed into the study.

- Previous immunosuppressive therapy

- The patient must have received no systemic immune suppressive therapy for
treatment of new acute GVHD (e.g. pentostatin, etanercept, denileukin difitox,
etc.), except for a maximum 120 hours prior corticosteroid therapy. This does not
include immune suppressive therapy for GVHD prophylaxis (e.g. calcineurin
inhibitor, sirolimus, MMF, etc.). It is expected that most patients will be
receiving GVHD prophylaxis as part of their transplant regimen, thus patients
developing acute GVHD while on GVHD prophylaxis will still be considered
eligible. Concurrent or addition of locally-acting steroid therapy (skin creams,
oral budesonide, or any other locally-acting steroid preparation) is allowed.

- There is one exception to the above stipulations: Use of the oral medication MMF
(in addition to systemic corticosteroids) for the treatment of acute GVHD will be
allowed. MMF is commonly given early in the treatment of acute GVHD, but it has
not been shown to improve outcomes compared to steroids alone in a randomized,
prospective study; therefore, treatment with MMF will not exclude patients from
BMSC treatment.

- Age: Age greater than or equal to 4 years old will be allowed.

- 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.

- Informed consent: Signed informed consent and/or assent is required. Assent and
educational materials will be provided to, and reviewed with, patients under the age
of 18. The informed consent process will begin at recognition of patient eligibility.

EXCLUSION CRITERIA:

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

- Known allergy to gentamicin.