Anti-CD19 CAR in PiggyBac Transposon-Engineered T Cells for Relapsed/Refractory B-cell Lymphoma or B-cell Acute Lymphoblastic Leukemia

Study Overview
=================
Brief Summary
-----------------
Our previous study demonstrated that anti-CD19 chimeric antigen receptor in piggyBac transposon-engineered T cells have strong tumor-killing activity in vitro and therapeutic effects in cell line-derived xenograft models, and no obvious side effects such as neurotoxicity and cytokine storm occurred. Therefore, we want to evaluate the safety and clinical effect of anti-CD19 CAR-T cells in clinical trials.

Detailed Description
-----------------
Using piggyBac transposon/transposase system to deliver genes into primary human T cells - example expression of CD19 CAR.CARs specific to the human CD19 antigen were used. All CARs contained the scFv against human CD19 (clone FMC-63), The third BBz CD28z CAR consisted of the scFv linked to the intracellular domains of CD28, 4-1BB and CD3z through a CD28 transmembrane domain; Subjects with relapsed/refractory CD19-positive B-cell Lymphoma or B-ALL can participate if all eligibility criteria are met. All patients received chemotherapy with fludarabine and cyclophosphamide before the infusion of anti-CD19 CAR-T cells.. After the infusion, subjects will accept follow-up for side effects and effect of anti-CD19 CAR-T cells. Follow-up : Safety and adverse events (safety and tolerability of anti-CD19 CAR-T cell therapy within 14 days): The number and severity of adverse events, an evaluation of their association with the anti-CD19 CAR-T cell treatment, and the outcome of the adverse events. Possible adverse events include cytokine release syndrome, hypotension, reversible neurotoxicity, hypogammaglobulinemia, etc. CT was used to evaluate B-lymphoma lesions. B-ALL bone marrow samples were collected by bone marrow aspiration to assess minimal residual disease. Flow cytometry was used to detect proportion of T cells, B cells, and NK cells in the blood, and expression of CD3, CD4, CD8, anti-CD19 CAR to determine the effect of anti-CD19 CAR-T treatment. Plasma levels of the cytokines IFN-gamma, TNF-α, IL-2, GM-CSF, IL-10, and IL-6 were also determined. Data analysis: Overall survival and progress free survival were determined by the Kaplan-Meier method, using all enrolled patients to determine overall survival. Study procedures may be performed while hospitalized.

Official Title
-----------------
A Phase I Clinical Trial of Anti-CD19 Chimeric Antigen Receptor in PiggyBac Transposon-Engineered T Cells for the Treatment of Patients With Relapsed/Refractory/High-risk B-cell Lymphoma or B-cell Acute Lymphoblastic Leukemia

Conditions
-----------------
B Cell Lymphoma, B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Biological: Anti-CD19 CAR-T Cells Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients or their legal guardians voluntarily participate and sign the Informed Consent Document; Male or female patients aged 18 to 70 years (inclusive); Pathologically and histologically confirmed CD19 + B cell tumors; Patients currently have no effective treatment options, such as chemotherapy or relapse after hematopoietic stem cell transplantation; Or patients voluntarily choose transfusion of anti-CD19 CAR-T cells as the first treatment program; B-cell tumors / lymphomas and B-cell acute lymphoblastic leukemia include the following four types:1) B-cell acute lymphoblastic leukemia;2) Indolent B-cell lymphomas;3) Aggressive B-cell lymphoma; 4) Multiple myeloma; Subjects: (1) Residual lesions remain after treatment and Not suitable for Hematopoietic stem cell transplantation (auto/allo-HSCT); (2) Relapse after Complement receptor 1 (CR1) and unsuitable for HSCT; (3) Patients with high risk factors; (4) Relapse or no remission after hematopoietic stem cell transplantation or cell immunotherapy. 6. Have measurable or evaluable tumor foci; 7. Liver, kidney and cardiopulmonary functions meet the following requirements: 1) Serum glutamic pyruvic transaminase (ALT) and serum glutamic oxaloacetic transaminase (AST) <3 ×upper limit of normal (ULN);2) Total bilirubin ≤34.2μmol/L;3) Serum creatinine<220μmol/L;4) Baseline oxygen saturation≥95%;5) Left ventricular ejection fraction（LVEF）≥40%. 8. Subjects who did not receive Chemotherapy, Radiotherapy, Immunotherapy (immunosuppressive drugs) or other treatment within 4 weeks prior to enrollment; Relevant toxicity≤1 grade before enrollment (except for low toxicity such as hair loss); 9. Peripheral superficial venous blood flow is smooth, which can meet the needs of intravenous drip; 10. Clinical performance status of eastern cancer cooperation group (ECOG) score ≤2,Expected survival≥3 months; Exclusion Criteria: Pregnant (urine/blood pregnancy test positive) or lactating women; Planned pregnancy during treatment or within 1 year after treatment, or a male subject whose partner plans pregnancy within 1 year of their cell transfusion; Patients cannot guarantee effective contraception (condom or contraceptives, etc.) within 1 year after enrollment; Active or uncontrollable infection within four weeks prior to enrollment; Patients with active hepatitis B/C; HIV-infected patients; Severe autoimmune or immunodeficiency disorders; Patients are allergic to macromolecule drugs such as antigens or cytokines; Subjects participated in other clinical trials within 6 weeks before enrollment; Systematic use of hormones within 4 weeks prior to enrollment (except for inhaled hormones); Mental illness; Drug abuse/addiction; The investigators consider other conditions unsuitable for enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-CD19 CAR-T Cells Injection<br>Anti-CD19 CAR-T Cells Injection, Dosage form：injection Dosage:1-2.5x10^6/kg, 100ml/time, The CAR-T cells will be administered by i.v. injection over 20-30 minutes, Frequency: total one time | Biological: Anti-CD19 CAR-T Cells Injection<br>* Dosage form：injection Dosage:1-2.5x10^6 cells/kg, 100ml/time, The CAR-T cells will be administered by i.v. injection over 20-30 minutes, Frequency: total one time<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade and number of cytokine release syndrome and neurotoxic effects in participants receiving treatment | Anti-CD19 CAR-T cells growing use requires further education/training and prompt management of safety and tolerability. | 14 day | 
| Persistence of anti-CD19 CAR-T cells in participants | Copies numbers of CAR in peripheral blood (PB) | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | For all subjects, overall survival refers to the period from being included in the test group to death caused by any reason | 3 years | 
| Progress Free Survival | Progression-free survival refers to the period between the start of treatment for participants and the observation of disease progression or death for any reason. | 3 years | 
| Duration of Response after administration | Duration of Response after administration | 3 years |