Autologous Stem Cell Transplantation for Crohn's Disease

Crohn's disease is considered to be an immune-mediated disease of the intestinal tract,
typically treated using immune modulating or immune suppressive therapies. These treatments
include local anti-inflammatory agents such as 5 aminosalicylic acid products, broad immune
suppression using corticosteroids, azathioprine, or methotrexate; cytokine suppression such
as antibody against TNFα; IL-12 and antibiotics such as ciprofloxacin and metronidazole that
work by decreasing the putative antigen exposure to the intestine. There is little in the
literature available on mortality data related to Crohn's Disease, but one series by Farmer
et al showed 6% mortality attributable to Crohn's disease. The mortality rate for selective
patients with refractory and severe disease is probably higher.

This protocol is based on the premise that the sustained inflammation of the GI tract that is
characteristic of Crohn's disease is the result of defective mucosal T cell tolerance. The
mucosal tolerance is normally maintained by CD4 + T cells characterized as T helper 3 (Th3)
and T regulatory 1 (TR1) T cell clones producing TGFβ and IL-10 respectively. There has been
much speculation on a possible infectious etiology of IBD implicating primarily mycobacterial
organisms, though despite extensive research no pathogenic organisms have definitively been
identified. In genetic cytokine knockout animal models of IBD, the typical nonpathogenic
enteric flora is sufficient to induce a chronic inflammatory reaction. Autoreactive T cells
appear to have broken through the mucosal tolerance with characteristic T helper 1 cytokine
profile secreting IL-1 and IFNγ.

In theory the most efficient approach to eradicate autoimmune T cell clones is through
replacement of the defective immune system with hematopoietic stem cells (HSC) from a healthy
allogeneic donor. However, the risks of morbidity and mortality associated with allogeneic
HSC transplantation currently do not appear to be justified even in treatment of refractory
cases of Crohn's disease. An alternative approach is to use autologous HSC from which
potential autoreactive T-cells have been eliminated, based on the hypothesis that from the
T-cell depleted autologous graft reconstitution of normal immunity will occur without
regeneration of autoimmune clones. Pilot trials in Crohn's and other autoimmune diseases have
confirmed the validity of this hypothesis. T-cells in the CD34 selected PBSC product are
significantly depleted. If active disease recurs despite intensive immunoablation, it is
likely that either CD34 selection did not adequately remove cells responsible for the
autoreactive state, or that the emerging genetically predisposed immune system was re-exposed
to autoantigens.

Unlike allogeneic transplants, the autologous transplant approach has greatly reduced
morbidity and mortality due to the absence of graft rejection and graft versus host disease
reactions. Currently, autologous HSCT demonstrate that transplant-related mortality is around
5% when transplanted for acute leukemia.

5.1 Inclusion Criteria

1. Subject and/or guardian must be able to understand and provide informed consent.

2. Male or female, 10 through 60 years old, inclusive at time of informed consent.

3. Examples of subjects for whom stem cell transplant therapy would be appropriate
include, but are not limited to:

- Patients who have had prior surgery and subsequent severe recurrent disease in
spite of aggressive maintenance therapy, necessitating consideration of further
extensive surgical resections.

- Patients who have diffuse small bowel and colonic disease and who are refractory
to aggressive medical treatment, and not eligible for treatment using a surgical
approach without the risk of precipitating short bowel syndrome and dependence of
parenteral nutrition or who have other conditions that preclude surgery

- Patients with a persistently high Harvey Bradshaw Index (HBI) (>6), CDAI (>250)
or Pediatric CD Activity Index (PCDAI>45) (44) score or those in the lower,
moderate range (HBI ≤ 6), (CDAI < 250), (PCDAI 30-45), but who are dependent on
daily doses of corticosteroids, that are unable to be withdrawn, and aggressive
medical treatment to maintain moderate disease status.

- Patients who have resistant complications of CD unresponsive to medical
management including multiple enteric fistulas, enterovesicular or enterovaginal
fistulas, severe perianal disease, debilitating arthritis, severe skin lesions
(pyoderma), and severe bony complications of the disease and therapy (aseptic
necrosis, pathologic fractures).

- Patients who developed severe complications to while receiving medical management
such as pancreatitis following 6-Mercaptopurine, colitis following 5-ASA or those
with severe hypersensitivity to TNFalpha inhibitors (infliximab, adalimumab,
certolizumab pegol), anti-integrin agents (natalizumab, vedolizumab) or
anti-IL12/23 agents (ustekinumab).

- Patients with stomas are eligible.

4. No surgical therapeutic option secondary to risk of short bowel syndrome or patient
refusal.

5. Harvey Bradshaw Index (HBI) or CD activity score >5, CDAI >250 or PCDAI >30.

6. Platelet count greater than 100,000/mm3.

7. Absolute neutrophil count greater than 1500/mm3 (unless secondary to 6MP therapy).

8. Creatinine ≤ 2.0 mg/dL.

9. No history of coronary artery disease; resting LVEF ≥ 40% or shortening fraction ≥
26%.

10. FEV1/FVC ≥ 60% predicted for age; DLCO ≥ 60% predicted value for age.

11. Negative pregnancy test for females ≥ 10 years old or who have reached menarche,
unless surgically sterilized.

12. All females or childbearing potential and sexually active males must agree to use a
FDA approved method of birth control for up to 24 months after PBSC transplant or for
as long as they are taking any medication that may harm a pregnancy, an unborn child
or may cause a birth defect.

5.2 Exclusion Criteria

1. Patients who have not been treated with adequate dosing of 6-MP, 5-ASA products and
metronidazole.

2. Patients who achieved a sustained, corticosteroid free response to anti-TNF alpha
therapy, anti-integrin therapy or anti-IL12/23 therapy after a 4 month course of
treatment.

3. Toxic megacolon, intestinal perforation

4. Conjugated bilirubin > 2.0 mg/dL.

5. Pregnancy or nursing mother

6. HIV/HTLV seropositive, HBsAg, or HCV RNA positive by PCR

7. Active infection, as determined by the appropriate confirmatory testing e.g. blood
cultures, PCR testing, etc., within two weeks of mobilization and high dose
chemotherapy.

8. Past or current medical problems or findings from physical examination or laboratory
testing that are not listed above, which, in the opinion of the investigator, may pose
additional risks from participation in the study, may interfere with the participant's
ability to comply with study requirements or that may impact the quality or
interpretation of the data obtained from the study.