Haploidentical Hematopoietic Cell Transplantation Using TCR Alpha/Beta and CD19 Depletion

T-Cell Receptor Alpha Beta+/CD19+ Depletion in Haploidentical Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) for Adult and Pediatric Patients With Hematological Malignancies and Non-malignant Disorders

Patients with medical conditions requiring allogeneic hematopoietic cell transplantation (allo-HCT) are at risk of developing a condition called graft versus host disease (GvHD) which carries a high morbidity and mortality. This is a phase I/II study that will test the safety and efficacy of hematopoietic cell transplantation (HCT) with ex-vivo T cell receptor Alpha/Beta+ and CD19 depletion to treat patients' underlying condition. This process is expected to substantially decrease the risk of GvHD thus allowing for the elimination of immunosuppressive therapy post-transplant. The study will use blood stem/progenitor cells collected from the peripheral blood of parent or other half-matched (haploidentical) family member donor. The procedure will be performed using CliniMACS® TCRα/β-Biotin System which is considered investigational.

This is a phase I/II study of haploidentical HCT (HHCT) with ex vivo TCRαβ+ and CD19+ depletion using the CliniMACS device in patients with hematological malignancies and non-malignant disorders. HHCT will be performed according to current standards of care at the Center for Cell and Gene Therapy (CAGT) within Texas Children's Hospital (TCH) and Houston Methodist Hospital (HMH), including the use of a standard chemotherapy conditioning regimens, supportive care and standard follow-up laboratory assessments. The study will determine efficacy of this strategy in terms of engraftment, and safety in terms of rates of acute and chronic graft versus Host Disease (GvHD), one-year overall survival (OS) and transplant-related mortality (TRM).

The peripheral blood hematopoietic cell product will undergo negative selection of TCR αβ following the standardized protocol in the user's manual for the CliniMACS (Miltenyi Biotech, Germany). TCR αβ+ T-cells are labeled by CliniMACS TCR αβ-Biotin (murine anti-TCR αβ monoclonal antibodies conjugated to biotin) which allows the TCR αβ+ T-cells to be magnetically labeled with CliniMACS Anti-Biotin Microbeads (murine anti-biotin monoclonal antibodies conjugated to superparamagnetic iron dextran particles) for depletion. The CD19+ B cells are labeled by CliniMACS CD19 microbeads which allows the CD19+ B cells to be magnetically labeled for depletion. All unlabeled cells are selected as target cells which should contain a minimum amount of TCR αβ+ and CD19+ cells. The microbeads used for labeling are approximately 50 nanometers in diameter and do not require removal prior to patient infusion.

In January 2014, the U.S. Food and Drug Administration (FDA) has approved the Miltenyi Biotec's CliniMACS CD34 Reagent System as a Humanitarian Use Device for the prevention of GvHD in patients with acute myeloid leukemia (AML) in first complete remission undergoing allo-HCT from HLA-matched related donor.

Inclusion Criteria:

1. Lack of suitable conventional donor (10/10 HLA matched related or unrelated donor) or presence of rapidly progressive disease not permitting time to identify an HLA-matched unrelated donor. This does not include cord blood unit (CBU) availability.

2. Lansky/Karnofsky score > 50

3. Signed written informed consent

4. Diagnosis of one of the following:

   1. Patient with life threatening hematological malignancy including "high-risk" ALL in first complete remission (CR1); ALL in second or subsequent remission (greater than or equal to CR2); high-risk AML in CR1; AML in second or subsequent CR; myelodysplastic syndromes (MDS); non-Hodgkin's lymphomas (NHL) in second or subsequent remission (greater than or equal to CR2); CML
   2. Hemophagocytic Lymphohistiocytosis (HLH) including familial HLH, relapsed HLH or central nervous system (CNS) HLH
   3. Primary Immunodeficiency Disorders (PID)
   4. Hemoglobinopathies including thalassemia or sickle cell disease (SCD)
   5. Severe aplastic anemia (SAA) not responding to immune suppressive therapy
   6. Congenital/hereditary cytopenias including Fanconi anemia (FA) without malignant clonal evolution (MDA, AML)
   7. Other inherited bone marrow failure syndromes (IBMFS)
   8. Sever chronic active Epstein Barr virus infection (SCAEBV) with predilection for T-or NK-cell malignancy

NOTE: 'High risk' ALL or AML refers to those acute leukemias identified by the presence of specific biologic features, which predict high likelihood of failure to conventional chemotherapy. As biologic features of high-risk disease evolve with improvement of conventional chemotherapy, it is not practical to define this indication with any further specificity. Therefore, high risk AML/ALL will be determined by the primary physician.

Exclusion Criteria:

1. Life expectancy of less than or equal to 6 weeks
2. Greater than grade II acute graft versus host disease (GVHD) or chronic extensive GVHD due to a previous allograft at the time of inclusion
3. Subject receiving an immunosuppressive treatment for GVHD treatment due to a previous allograft at the time of inclusion
4. Symptomatic cardiac disease or left ventricular shortening fraction less than 25% or ejection fraction < 40%
5. Severe renal disease, with creatinine clearance < 40cc/1.73m2
6. Pre-existing severe restrictive pulmonary disease, FVC < 40% of predicted
7. Severe Hepatic Disease with ALT/AST ≥ x 2.5 upper limit of normal or bilirubin level ≥ x 1.5 upper limit of normal
8. Serious concurrent uncontrolled medical disorder or mental illness
9. Pregnant or breastfeeding female subject
10. Current active infectious disease including viral and fungal diseases at the time of enrollment; that on evaluation of PI precludes ablative chemotherapy or successful transplantation
11. Active HIV infection
12. Severe personality disorder or mental illness that would preclude compliance with the study