Humanized CD19 Chimeric Antigen Receptor (CAR)-Modified T Cell Therapy in Treating Patients With B-cell Malignancies

Study Overview
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Brief Summary
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This is a single arm, open-label study to evaluate the safety and efficacy of humanized anti-CD19 CAR-T cells in patients with relapsed or refractory B cell Malignancies.

Detailed Description
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Chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) have the capabilities to recognize tumor associated antigen and kill tumor cells specifically. CAR-T therapy showed great effect on patients with relapsed or refractory B cell malignancies. To improve the efficacy and safety, the researchers designed a second-generation humanized CAR, consisting of humanized CD19 single chain variable fragment (scFv) and CD137 costimulatory domain. This study aims to evaluate the safety and effectiveness of humanized anti-CD19 CAR-T cells in patients with relapsed or refractory B cell Malignancies.

Official Title
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Treatment of Relapsed or Refractory B-cell Malignancies by Humanized CD19 Chimeric Antigen Receptor (CAR)-Modified T Cells

Conditions
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Acute Lymphoblastic Leukemia, B Cell Lymphoma

Intervention / Treatment
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* Genetic: Second generation humanized CAR-T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient is pathologically and histologically confirmed as CD19 + B cell tumors, and has no effective treatment options currently, such as chemotherapy; or relapsed after auto-HSCT/allo-HSCT; or patients voluntarily choose CD19 CAR-T cells as a first treatment; B cell hematological malignancies include the following three categories: A. B-cell acute lymphocytic leukemia (B-ALL); B. Indolent B-cell lymphoma (CLL, FL, MZL, LPL); C. Aggressive B-cell lymphoma (DLBCL, BL, MCL); Aged from 14 to 70 years old; Expected survival time > 6 months; Female patients around childbearing age, negative pregnancy test before trial, and agreed to take effective contraceptive measures during the trial until the last visit; Voluntarily participate in this experiment and sign informed consent by themself, or legally authorized representative. Exclusion Criteria: With a history of epilepsy or other central nervous system diseases; Having graft-versus-host reaction, requires the use of immunosuppressants; The presence of clinically significant cardiovascular disease, such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within recent six months, or heart disease with cardiac function in any grade 3 (moderate) or 4 ( severe) (according to the New York Heart Association (NYHA) Functional Classification System); Pregnant or lactating women (safety of this therapy for the unborn child is unknown); Not curable active infection; Patients with active hepatitis B or hepatitis C virus infection; Combined use of systemic steroids within two weeks (except use of inhaled steroid recently or currently); Using product of gene therapy before; Creatinine> 2.5 mg / dl (221.0 umol/L); ALT / AST> 3 X the normal amount; Bilirubin> 2.0 mg / dl (34.2 umol/L); Patients suffering from other uncontrolled diseases, and researchers believe that the patient is not suitable for trial; Patients with HIV-infection; Any situation that may increase the risk of patients or interfere with test results.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 70 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: Second generation humanized CAR-T cells<br>Patients receive humanized CD19 CAR-T cells transduced with a lentiviral vector on days 0/1/2 in the absence of disease progression or unacceptable toxicity. | Genetic: Second generation humanized CAR-T cells<br>* Patients receive humanized CD19 CAR-T cells transduced with a lentiviral vector on days 0/1/2 in the absence of disease progression or unacceptable toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | Therapy-related adverse events were recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0) | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-month remission rate | Response of B-ALL to CAR-T therapy was assessed on day 30 (±2), against the National Comprehensive Cancer Network (NCCN, Version 1.2015). | 1 month | 
| Overall survival | OS was calculated from the first CAR-T cell infusion to death or last follow-up (censored). | 5 years | 
| Event-free survival | EFS was calculated from the first CAR-T cell infusion to death, progression of the disease, relapse or gene recurrence, whichever came first, or last visit (censored). | 5 years | 
| Relapse-free survival | RFS was calculated from the first CAR-T cell infusion to relapse or last visit (censored). | 5 years | 
| Rate of anti-CD19 CAR-T cells in bone marrow cells and peripheral blood cells | In vivo (bone marrow and peripheral blood) rate of CAR-T cells were determined by means of flow cytometry. | 5 years | 
| Quantity of anti-CD19 CAR-T cells in bone marrow cells and peripheral blood cells | In vivo (bone marrow and peripheral blood) quantity of CAR-T cells were determined by means of flow cytometry. | 5 years | 
| Quantity of anti-CD19 CAR copies in bone marrow cells and peripheral blood cells | In vivo (bone marrow and peripheral blood) quantity of anti-CD19 CAR copies were determined by means of qPCR. | 5 years |