Evaluation of 4th Generation Safety-designed CAR T Cells Targeting High-risk and Refractory B Cell Lymphomas

Study Overview
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Brief Summary
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Currently, a majority of B cell lymphomas cannot be cured by standard chemo-radiotherapy. Most B cell lymphomas express cluster of differentiation antigen 19 (CD19), which represents a very attractive target for chimeric antigen receptor (CAR)-based immune cell therapy. This study will evaluate a novel 4th generation CD19 CAR engineered with a self-withdrawal mechanism (19273-4SCAR) for both efficacy and safety in lymphoma patients.

Detailed Description
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CD19 single chain antibody-based chimeric antigen receptor (CAR)-engineered T cells have demonstrated great clinical potential in treating chronic and acute B cell leukemias. B cell lymphomas, similar to B cell leukemias, express CD19 surface molecules, and the majority of the B cell lymphoma patients cannot be cured by standard chemo-radiotherapy. CD19 CAR-based adoptive T cell therapy is associated with an unwanted adverse effect, the loss of CD19 B cells, which results in humoral immune deficiency. This study will evaluate a novel 4th generation CD19 CAR engineered with a self-withdrawal genetic mechanism (19273-4SCAR) for both efficacy and safety in lymphoma patients. The 4th generation design of the CAR incorporates the intracellular signaling domain of cluster of differentiation antigen 27 (CD27), known to be associated with T cell activation, survival and longevity. The inducible caspase 9 self-withdrawal design allows for rapid elimination of the infused CAR T cells upon complete eradication of the tumor cells, which will be followed by the recovery of humoral immunity. Patients receiving the 19273-4SCAR T cells will be closely monitored for infusion response, tumor eradication effect, longevity of the CAR T cells, and the recovery of B cell functions after withdrawal of the CAR T cells.

Official Title
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Safety and Efficacy Evaluation of 4th Generation Safety-engineered CAR T Cells Targeting High-risk and Refractory B Cell Lymphomas

Conditions
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B-cell Lymphomas

Intervention / Treatment
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* Genetic: Anti-CD19 CAR T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory CD19(+) B cell lymphoma patients proved by immuno-histochemistry (IHC) or Flow-cytometry. Not eligible for autologous stem-cell transplantation (ASCT) or relapsed after ASCT. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Age≥18. Pulse oximetry of > 90% on room air. Adequate hepatic function, defined as alanine transaminase (ALT) <3 x upper limit of normal (ULN), aspartate aminotransferase (AST) <3 x ULN; serum bilirubin and alkaline phosphatase <2 x ULN. Adequate renal function, defined as serum creatinine <2.0mg/dl. Adequate heart function with LVEF≥50% Hb≥80g/L Measurable disease can be identified. Life expectancy ≥3 months. Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 1 year after the study is concluded. The male partner should use a condom. Patients must sign an informed consent. Exclusion Criteria: Uncontrolled active infection. Active infection with hepatitis B virus (HBV), hepatitis C virus (HCV). HIV positive Pregnant or lactating. Currently enrolled in another clinical trial. Concurrent use of systemic steroids.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR T cells<br>Autologous 4th generation anti-CD19-CAR T cells | Genetic: Anti-CD19 CAR T cells<br>* Autologous 4th generation withdrawable lentiviral-transduced anti-CD19-CAR T cells<br>* Other names: 19273-4SCAR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events. | Determine the toxicity profile of the 4th generation CAR T cells with Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.0. | 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival time of Anti-CD19 CAR T cells in vivo. | Measure the survival of 4th generation CAR T cells transduced with the anti-CD19 lentiviral vector. | 2 years. | 
| Response rates to the 4th generation CAR T cells. | Describe the response rates of patients treated with 4th generation CAR T cells, including partial remission (PR), complete remission (CR), stable disease (SD) and progressive disease (PD). | 2 years. | 
| Survival time of the patients. | Evaluate the survival time of the patients treated with the 4th generation CAR T cells, including progression free survival (PFS) and overall survival (OS). | 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B cell lymphoma, non-Hodgkin's lymphoma, Burkitt lymphoma, diffused large B cell lymphoma, B cell malignancy