CELL INTELLIGENCE · 肿瘤细胞治疗研究

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

主要终点：Cumulative Incidence of Neutrophil Engraftment and Platelet Engraftment · Cumulative incidence of neutrophil and platelet engraftment (composite measure) will be reported as rate and its associated 95% confidence interval. Competing risks methods will be utilized, with graft failure and death considered as competing risks. Neutrophil engraftment is defined as the first of 3 consecutive days with a peripheral blood absolute neutrophil count of ≥ 0.5x10\^9/L Platelet engraftment is defined as the first day with platelet count of ≥ 20 x10\^9/L without transfusion support for 7 consecutive days · 42 days post-HCT；Cumulative Incidence of Grade III or Higher Acute GVHD · Cumulative incidence of grade III or higher acute GVHD among patients who achieve engraftment will be reported as rate and its associated 95% confidence interval. Competing risks methods will be utilized, with death considered the competing risk. · 100 days post-HCT
次要终点：Cumulative Incidence of Transplant-related Mortality (TRM)；Overall Survival (OS)；Cumulative Incidence of Chronic Graft Versus Host Disease

• Alpha beta+ T cell depleted CD34+ stem cells · EXPERIMENTAL · The patient will be receiving a donor stem cell transplant with a preceding conditioning regimen (chemotherapy with, or without, radiation). The investigators will be specially treating the donor's blood cells used for the stem cell transplant.

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.