MeCAR: Memory-enriched CAR-T Cells Immunotherapy for B Cell Lymphoma
Study Details
Study Description
Brief Summary
The goal of this clinical trial is to study how approaches for manufacturing chimeric antigen receptor (CAR)-modified T (CAR-T) cells affect their in vivo persistence and therapeutic efficacy against B lymphoma. Recently, cancer immunotherapy, treatments aiming to arm patients with immunity specifically against cancer cells, has emerged as a promising therapeutic strategy. Among the many emerging immunotherapeutic approaches, clinical trials utilizing CARs against B cell malignancies have demonstrated remarkable potential. CARs combine the variable region of an antibody with T-cell signaling moieties to confer T-cell activation with the targeting specificity of an antibody. Thus, CARs are not MHC-restricted so they are not vulnerable to MHC down regulation by tumors. However, defined by the activation and contraction program of their mother cells, the persistency and function of CAR-T cells are also restricted by the protocol of manufacturing. Previous clinical studies largely utilized interleukin-2 (IL-2) for the ex vivo expansion of CAR-T cells, which preferentially generate CAR-T cells with characteristics of terminally differentiated effector cells. Our preliminary data indicated that two common gamma chain cytokines, IL-7 and IL-15, can help to selectively expand CAR-T cells with various memory phenotypes. CAR-T Cells prepared under this condition resulted in improved therapeutic efficacy in preclinical animal models. This clinical investigation is to test a hypothesis whether IL-7/IL-15-programmed anti-CD19 CAR-T cells persist longer in lymphoma patients after infusion and whether the persistency of CAR-T cells can lead to improved anti-lymphoma efficacy.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1/Phase 2 |
Detailed Description
Primary Objectives
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To determine the safety and feasibility of CD19.CAR-T cells manufactured through IL-7/IL-15-mediated expansion or IL-2-mediated expansion
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To determine in vivo dynamics and persistency of IL-7/IL-15 programmed CD19.CAR-T cells.
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To determine the efficacy of IL-7/IL-15 programmed CD19.CAR-T cells in treating patients with CD19-positive lymphoma
Secondary Objectives
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To determine whether the IL-7/IL-15 programmed CD19.CAR-T cells are superior to the IL-2 programmed cells as measured by their in vivo persistence post infusion
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To determine whether the IL-7/IL-15 programmed CD19.CAR-T cells are superior to the IL-2 programmed cells as measured by their efficacy in lymphoma therapy
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To assess the dynamics of intratumoral infiltration of CD19.CAR-T cells.
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To correlate the subsets and differentiation of CD19.CAR-T cells to observed anti-tumor efficacy
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: IL-2 programmed CD19.CAR-T cells Administrated with IL-2 programmed CD19.CAR-T cells on day 0,1,2 in the lympho-depleted patients |
Drug: CD19.CAR-T cells
Retroviral vector-transduced autologous T cells to express CD19-specific CARs
Other Names:
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Experimental: IL-7/IL-15 programmed CD19.CAR-T cells Administrated with IL-7/IL-15 programmed CD19.CAR-T cells on day 0,1,2 in the lympho-depleted patients |
Drug: CD19.CAR-T cells
Retroviral vector-transduced autologous T cells to express CD19-specific CARs
Other Names:
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Outcome Measures
Primary Outcome Measures
- Phase 1: Safety measured by occurrence of study related adverse effects defined by NCI CTCAE 4.0 [4 weeks]
- Phase 2: Overall complete remission rate defined by the standard response criteria for malignant lymphoma for each arm [8 weeks]
- Phase 2: Comparison of overall complete remission rate for the two arms [One year]
Secondary Outcome Measures
- Duration of remission [One year]
- Minimum residual disease negative remission rate [8 weeks]
- Duration of CAR-positive T cells in circulation [6 months]
- Total number of CAR-positive T cells infiltrated into lymphoma tissue [6 months]
- Overall survival [One year]
Eligibility Criteria
Criteria
Inclusion Criteria:
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18 Years to 70 Years, Male and female;
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Expected survival > 12 weeks;
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Performance score 0-2;
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Histologically confirmed as CD19-positive lymphoma and who meet one of the following conditions;
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Patient receive at least 2-4 prior combination chemotherapy regimens (not including single agent monoclonal antibody therapy) and fail to achieve CR; or have disease recurrence; or not eligible for allogeneic stem cell transplantation; or disease responding or stable after most recent therapy but refused further treatment;
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Disease recurrence after stem cell transplantation;
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Diagnosis as lymphoma, but refuse conventional treatment such as chemotherapy, radiation, stem cell transplantation and monoclonal antibody therapy
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Creatinine < 2.5 mg/dl;
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ALT/AST < 3x normal;
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Bilirubin < 2.0 mg/dl;
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Adequate venous access for apheresis, and no other contraindications for leukapheresis;
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Take contraceptive measures before recruit to this trial;
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Written voluntary informed consent is given.
Exclusion Criteria:
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Patients with symptoms of central nervous system
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Accompanied by other malignant tumor
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Active hepatitis B or C, HIV infection
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Any other diseases could affect the outcome of this trial
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Suffering severe cardiovascular or respiratory disease
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Poorly controlled hypertension
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A history of mental illness and poorly controlled
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Taking immunosuppressive agents within 1 week due to organ transplantation or other disease which need long-lasting administration
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Occurrence of unstable pulmonary embolism, deep vein thrombosis, or other major arterial/venous thromboembolic events 30 days prior to assignment
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Reaching a steady dose if receiving anticoagulant therapy before assignment
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Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
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Pregnant or lactating women
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Subject suffering disease affects the understanding of informed consent or comply with study protocol.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Department of Oncology | ChongQing | Chongqing | China | 400000 |
Sponsors and Collaborators
- Xinqiao Hospital of Chongqing
- Xuzhou Medical University
- Hrain Biotechnology Co., Ltd.
- Shanghai Changzheng Hospital
Investigators
- Principal Investigator: Bo Zhu, M.D., Ph.D., Department of Cancer of Xinqiao Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 20151117