Cord Blood Derived Anti-CD19 CAR-Engineered NK Cells for B Lymphoid Malignancies
Study Details
Study Description
Brief Summary
This is a single-center, open-label, single-arm study to evaluate the primary safety and efficacy of anti-CD19 chimeric antigen receptor(CAR)-modified NK cells(CAR-NK-CD19) in patients with relapsed or refractory hematological malignancies.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Detailed Description
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.
Cord blood(CB) derived NK cells from healthy donor are the source for production of CAR-NK-CD19 cells. CB derived NK cells are purified and transduced with a retroviral vector encoding the anti-CD19 CAR and interleukin-15.
This is an investigational study. The objectives are to evaluate the safety and efficacy of CAR-NK-CD19 cells in patients with CD19+ B-cell malignancies.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells Patients will received lymphodepletion with fludarabine (30 mg/kg) and cyclophosphamide (300 mg/kg) on day -5, -4, and -3, followed by one infusion of CAR-NK-CD19 cells on day 0. The study will be divided into three groups: Acute Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, and Non Hodgkin's Lymphoma. Doses of 0.01×10^7, 0.1×10^7, 1.0×10^7 CAR+ T cells (with an allowance of ±20%) will be tested in each group in the 3+3 dose-escalation study. Each dose group has 3 patients. If no dose-limited toxicity (DLT) emerges in the group, then the subsequent higher dose will be used in the next group. If DLT emerges in a single subject in any dose level, 3 more subjects will be enrolled to the same dose level. The maximum dose could be extended. |
Drug: Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells
fludarabine 30 mg/kg on day -5, -4, and -3; cyclophosphamide 300 mg/kg on day -5, -4, and -3; CAR-NK-CD19 Cells on day 0.
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Outcome Measures
Primary Outcome Measures
- Incidence of Treatment-related Adverse Events [within 2 years after infusion]
Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0).
Secondary Outcome Measures
- Overall response rate(ORR) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]
ORR will be assessed from CAR T cell infusion to death or last follow-up (censored).
- Complete response rate(CRR) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]
CRR will be assessed from CAR T cell infusion to death or last follow-up (censored).
- Progress-free survival(PFS) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]
PFS will be assessed from CAR T cell infusion to death or last follow-up (censored).
- Duration of Response(DOR) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]
DOR will be assessed from CAR T cell infusion to death or last follow-up (censored).
- Overall survival(OS) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]
OS will be assessed from CAR T cell infusion to death or last follow-up (censored).
Other Outcome Measures
- In vivo expansion and survival of CAR-NK-CD19 cells [within 2 years after infusion]
Quantity of CAR-NK-CD19 CAR copies in bone marrow and peripheral blood will be determined by using quantitative polymerase chain reaction.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Aged ≥ 18 years;
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Eastern Cooperative Oncology Group score≤ 3;
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Diagnosed as CD19+ B-cell hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and Non Hodgkin's lymphoma.
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Patients must relapse or be refractory after at least two lines of therapy.
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Patient's main organs functioning well:
- Liver function: alanine aminotransferase/aspartate aminotransferase < 2.5 times the upper limit of normal (ULN) and total bilirubin≤ 1.5 times ULN; B. Renal function: Creatinine clearance rate ≥ 60ml/min. C. Pulmonary function: Indoor oxygen saturation ≥ 95%. D. Cardiac Function: Left ventricular ejection fraction (LVEF) ≥50%, no clinically-significant ECG findings.
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Negativity of blood pregnancy test for woman, and participants use effective methods of contraception until last follow-up.
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Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.
Exclusion Criteria:
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Investigators judge the patients with gastrointestinal lymph node and/or central nervous system involvement who may be at high-risk of receiving CAR-NK-CD19 cell treatment.
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Patients with graft-versus-host reaction and need immunosuppressive agents, or patients with autoimmune diseases.
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Systemic steroids are used within 5 days before apheresis.
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Drugs to stimulate the production of bone marrow hematopoietic cells are used within 5 days before apheresis.
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Patients receive cytotoxic chemotherapy or radiotherapy within 21 days before enrollment(Tyrosine kinase inhibitors or other targeted therapies can be used two weeks before lymphodepleting chemotherapy).
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History of epilepsy or other central nervous system diseases.
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Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within five years.
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Known HIV positive patients.
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Patients with active infections, including active replication of hepatitis B or active hepatitis C.
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Patients receive any antitumor treatments within 4 weeks before enrollment, and the toxicity related to previous treatments don't return to < 1 level at enrollment (except for low grade toxicity such as alopecia).
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Major surgery in the past 4 weeks.
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Non-compliant patients.
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Anticoagulants are being used.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Union Hospital, Huazhong University of Science and Technology | Wuhan | Hubei | China | 430022 |
Sponsors and Collaborators
- Wuhan Union Hospital, China
- Shanghai Simnova Biotechnology Co.,Ltd.
Investigators
- Principal Investigator: Yu Hu, Wuhan Union Hospital, China
Study Documents (Full-Text)
None provided.More Information
Publications
- CAR-NK-CD19 cells