Competitive Transfer of αCD19-TCRz-CD28 and αCD19-TCRz-CD137 CAR-T Cells for B-cell Leukemia/Lymphoma

Study Overview
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Brief Summary
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This is a single-arm open-label phase I/II study to determine the relative superiority of αCD19-TCRζ-CD28 and αCD19-TCRζ-CD137 CAR-T Cells in safety, efficacy and engraftment potential in patients with CD19+ B-lineage leukemia and lymphoma. Recently, cancer immunotherapy, treatments aiming to arm patients with immunity specifically against cancer cells, has emerged as a promising therapeutic strategy. Clinical trials utilizing CARs against B cell malignancies have demonstrated remarkable potential. In this trial, all subjects will be competitively infused with αCD19-TCRz-CD28 and αCD19-TCRz-CD137 CAR-T cells in equal number to test a hypothesis that CD137-costimulation can promote the persistence and engraftment of CAR-T cells and this superiority can lead to improved progression-free survival.

Detailed Description
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Primary objectives 1. To determine the safety and feasibility of adoptive transfer of T cells modified to express CD19-specific chimeric antigen receptor (CD19CAR) for treatment of leukemia and lymphoma Secondary objectives To measure the efficacy of anti-tumor responses after CD19CAR T cell infusion To determine if CD19CAR T cells engineered with 4-1BB signaling domain is superior to that with CD28 signaling domain for their homing and persistence after CD19CAR T cell infusion

Official Title
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A Phase I/II Study of Competitive Transfer of αCD19-TCRz-CD28 and αCD19-TCRz-CD137 Chimeric Antigen Receptor T-Cells in Patients With Refractory CD19+ B-lineage Leukemia/Lymphoma

Conditions
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Hematopoietic/Lymphoid Cancer, Adult Acute Lymphoblastic Leukemia in Remission, B-cell Adult Acute Lymphoblastic Leukemia, B-cell Chronic Lymphocytic Leukemia, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Refractory Chronic Lymphocytic Leukemia, Stage III Adult Diffuse Large Cell Lymphoma, Stage III Chronic Lymphocytic Leukemia, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Chronic Lymphocytic Leukemia, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma

Intervention / Treatment
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* Biological: anti-CD19 CAR-T
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 5 Years to 70 Years, Male and female; Expected survival > 12 weeks; Performance score 0-2; Histologically confirmed as CD19-positive lymphoma/leukemia and who meet one of the following conditions; 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; Disease recurrence after stem cell transplantation; Diagnosis as lymphoma, but refuse conventional treatment such as chemotherapy, radiation, stem cell transplantation and monoclonal antibody therapy Creatinine < 2.5 mg/dl; ALT/AST < 3x normal; Bilirubin < 2.0 mg/dl; Adequate venous access for apheresis, and no other contraindications for leukapheresis; Take contraceptive measures before recruit to this trial; Written voluntary informed consent is given. Exclusion Criteria: Patients with symptoms of central nervous system Accompanied by other malignant tumor Active hepatitis B or C, HIV infection Any other diseases could affect the outcome of this trial Suffering severe cardiovascular or respiratory disease Poorly controlled hypertension A history of mental illness and poorly controlled Taking immunosuppressive agents within 1 week due to organ transplantation or other disease which need long-lasting administration Occurrence of unstable pulmonary embolism, deep vein thrombosis, or other major arterial/venous thromboembolic events 30 days prior to assignment Reaching a steady dose if receiving anticoagulant therapy before assignment Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion Pregnant or lactating women Subject suffering disease affects the understanding of informed consent or comply with study protocol.

Ages Eligible for Study
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Minimum Age: 5 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: Mixed CD19CAR transfer<br>All subjects will be infused with αCD19-TCRz-CD28 and αCD19-TCRz-CD137 CAR-T cells in equal number | Biological: anti-CD19 CAR-T<br>* Ex vivo-expanded autologous T cells modified to express CD19 CAR<br>Drug: Fludarabine<br> <br> Drug: Cyclophosphamide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (incidence of adverse events defined as dose-limited toxicity) |  | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall complete remission rate |  | 8 weeks | 
| Survival of CAR T cells in circulation measured by flow cytometry and PCR |  | 1 year | 
| Duration of remission |  | 1 year | 
| Overall survival |  | 1 year |