Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases

This is an original IND for an investigator initiated phase I/II study. The primary purpose
of the study is to evaluate the safety and efficacy of performing bilateral orthotopic lung
transplantation (BOLT) followed by cadaveric, partially HLA-matched CD3+/CD19+-depleted
hematopoietic stem cell transplantation (HSCT) from the same donor for patients with primary
immunodeficiency diseases (PID) and end-stage lung disease. For many patients with primary
immunodeficiencies, HSCT is a curative, life-saving therapy, resulting in restoration of
function in the immune system. Patients with primary immunodeficiencies often develop
pulmonary complications as a result of chronic or recurrent infections, making them
ineligible for HSCT due to the high risk of mortality and pulmonary complications. Lung
transplant prior to HSCT would allow for restoration of pulmonary function prior to HSCT,
allowing PID patients to proceed to HSCT, which would be curative for the patient's
underlying immunodeficiency. As a secondary aim after successful engraftment with donor bone
marrow, there is realistic hope for tolerating planned withdrawal of immunosuppression
achieving eventual freedom from all immunosuppressive drugs and attaining a tolerant state.

Inclusion Criteria

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

2. Male or female, 5 through 45 years old, inclusive, at the time of informed consent.

3. Patients must have evidence of an underlying primary immunodeficiency for which BMT is
clinically indicated.

Examples of such diseases include, but are not limited to:

- Severe Combined Immunodeficiency

- Combined immunodeficiency with defects in T-cell-mediated immunity, including
Omenn syndrome and DiGeorge Syndrome

- Severe Chronic Neutropenia

- Chronic Granulomatous Disease

- Hyper IgE Syndrome or Job Syndrome

- CD40 or CD40L deficiency

- Wiskott-Aldrich Syndrome

- Mendelian Susceptibility to Mycobacterial Disease [6]

- GATA2 Associated Immunodeficiency NOTE: A genetic diagnosis is recommended, but
not required.

4. Patients must have evidence of end-stage lung disease and be candidates for bilateral
orthotopic lung transplant as determined by the lung transplant team.

5. GFR ≥ 50 mL/min/1.73 m2.

6. AST, ALT ≤ 4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL, normal INR.

7. Cardiac ejection fraction ≥ 40% or shortening fraction ≥26%.

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

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

10. Subject and/or parent guardian will also be counseled regarding the potential risks of
infertility following BMT and advised to discuss sperm banking or oocyte harvesting.

Exclusion Criteria

Individuals who meet any of these criteria are not eligible for this study:

1. Inability or unwillingness of a participant to give written informed consent or comply
with study protocol.

2. Patients who have underlying malignant conditions.

3. Patients who have non-malignant conditions not requiring hematopoietic stem cell
transplantation.

4. HIV positive by serology or PCR, HTLV positive by serology.

5. Females who are pregnant or who are lactating.

6. Allergy to DMSO or any other ingredient used in the manufacturing of the stem cell
product.

7. Uncontrolled pulmonary infection, as determined by radiographic findings and/or
significant clinical deterioration. NOTE: Pulmonary colonization with multiple
organisms is common, and will not be considered an exclusion criterion.

8. Uncontrolled systemic infection, as determined by the appropriate confirmatory testing
e.g. blood cultures, PCR testing, etc.

9. Recent recipient of any licensed or investigational live attenuated vaccine(s) within
4 weeks of transplant.

10. 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.

Eligibility Criteria to proceed to Bone Marrow Transplant

1. GFR ≥ 50 mL/min/1.73 m2.

2. AST, ALT ≤ 4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL.

3. Cardiac ejection fraction ≥ 40% or shortening fraction of at least 26%.

4. HIV negative by serology and PCR.

5. HTLV serology negative.

6. FVC and FEV1 ≥40% predicted for age and SpO2 of >90% at rest on room air AND with
clearance by the lung transplant team.

7. Absence of uncontrolled infection as determined by positive blood cultures and
radiographic progression of previous sites in particular pulmonary densities during
the past 2 weeks prior to chemotherapy.

8. Absence of clinically significant Acute Cellular Rejection (A2-A4 and/or B2R
rejection).