CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

The following criteria are used to enroll patients in the study before transplant.

* Patients with neoplastic hematological disorders with indication of allogeneic transplant according to the National Comprehensive Cancer Network (NCCN) or other standard guidelines as follows:

  * Acute myeloid leukemia \[AML\] in morphologic complete remission with intermediate/high-risk features (per NCCN criteria) or relapsed disease
  * Chronic myeloid leukemia \[CML\] in any chronic phase.
  * Myelodysplastic syndrome \[MDS\] with intermediate/high risk features or refractory disease (with bone marrow blast count \<10%).
  * Acute lymphoblastic leukemia \[ALL\] in morphologic complete remission with high-risk features or relapsed disease.
* Negative test for donor-specific antibody within 28 days of starting conditioning regimen.
* Age Criteria: 19-65 years.
* Organ Function Criteria: The following organ function testing should be done within 35 days before study registration.

  * Cardiac: Normal left ventricular ejection fraction (LVEF) (50% or above) as measured by MUGA or Echocardiogram.
  * Pulmonary: FVC, FEV1 and DLCO (corrected) should be 50% or above of expected.
  * Renal: serum creatinine level to be \<2 mg/dl AND estimated (Cockcroft-Gault formula) or measured (takes priority if done) creatinine clearance (CrCl) must be equal or greater than 70 mL/min/1.73 m2.
  * Hepatic: serum bilirubin 1.5 upper limit of normal (ULN), Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 ULN, and alkaline phosphatase 2.5 ULN.
* Performance status: Karnofsky performance score (KPS) or Lansky score: ≥80.
* Hematopoietic cell transplant comorbidity index (HCT-CI) \<3. Exception may be made on individual cases after discussion with the primary investigator.
* Consent: All patients must be informed of the investigational nature of this study and given written informed consent in accordance with institutional and federal guidelines.

The following criteria are required within 48 hours prior to infusion of the EAGD T cell product.

* Absence of uncontrolled infection with sepsis syndrome (e.g persistent positive blood culture).
* NO hemodynamic instability (due to sepsis or organ dysfunction) or circulatory volume overload.
* NO clinically significant organ toxicity that are defined as follows:

  * Heart failure with subnormal LVEF or clinical fluid overload.
  * Elevated serum creatinine or subnormal creatinine clearance (either estimated or measured).
  * Elevated total bilirubin ≥1.5 upper normal level (unless indirect hyperbilirubinemia attributed to non-hepatic pathology), or elevated liver enzymes (ALT, AST, ALP) \>5 x ULN.
  * Hypoxemia requiring oxygen therapy
* NO acute graft versus host disease (any grade).
* Neutrophil engraftment.

Exclusion Criteria:

* Non-compliant patients.
* No appropriate caregivers identified.
* Uncontrolled medical or psychiatric disorders which may preclude patients to undergo clinical studies (Discretion of the attending physician).
* Active central nervous system (CNS) neoplastic involvement.
* Morbid obesity with body mass index \>35 (borderline cases may be considered on case-by-case basis after discussion with the primary investigator).
* Patients with known allergy to DMSO.
* HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive.
* Pregnant or breastfeeding women.

主要终点：Phase I - Dose-limiting toxicity (DLT) · The dose escalation strategy will follow the Food and Drug Administration Guideline for design of early phase clinical trials of cellular therapy products. · Baseline to Day 30；Phase I - Severe acute adverse events following infusion of EAGD T-cells · Safety of the infusion will be based on the risk of treatment-related severe adverse events as identified in the National Cancer Common Terminology Criteria for Adverse Events (CTCAE) version 4. · Baseline to Day 100；Expansion phase - Rate of acute GVHD · Monitoring for GVHD is assessed with Grade II-IV adverse events as identified by the National Cancer Common Terminology Criteria for Adverse Events (CTCAE) version 4. · Baseline to Day 100
次要终点：Expansion phase - Relapse following haploidentical HCT and PTCy with EAGD T-cell infusion；Expansion phase - Non-relapse mortality following haploidentical HCT and PTCy with EAGD T-cell infusion；Expansion phase - Overall survival following haploidentical HCT and PTCy with EAGD T-cell infusion；Rate of one-year relapse-free survival (RFS)；Rate of one-year non-relapse mortality (NRM)；Rate of one-year overall survival (OS)；Proportion of subjects with chronic GVHD at one year

• EAGD T-cell infusion (Phase I) · EXPERIMENTAL · Peripheral blood is collected by leukapheresis from the donor, expanded and activated on CliniMACS-Prodigy, further depleted of alpha beta T-cells using the CliniMACS Alpha Beta T-Cell Depletion System, which leaves a gamma delta T-cell rich product. This product is then infused into the recipient at either 1, 3, or 10 x 1,000,000 cells/kg concentrations depending upon the cohort.
• EAGD T-cell infusion (Expansion) · EXPERIMENTAL · Peripheral blood is collected by leukapheresis from the donor, expanded and activated on CliniMACS-Prodigy, further depleted of alpha beta T-cells using the CliniMACS Alpha Beta T-Cell Depletion System, which leaves a gamma delta T-cell rich product. This product is then infused into the recipient at the maximum tolerated dose as determined from Phase I.

Gamma delta T-cells are part of the innate immune system with the ability to recognize malignant cells and kill them. This study uses gamma delta T-cells to maximize the anti-tumor response and minimize graft versus host disease (GVHD) in leukemic and myelodysplastic patients who have had a partially mismatched bone marrow transplant (haploidentical).