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.

Primary Objectives

1. To determine the safety and feasibility of CD19.CAR-T cells manufactured through IL-7/IL-15-mediated expansion or IL-2-mediated expansion
2. To determine in vivo dynamics and persistency of IL-7/IL-15 programmed CD19.CAR-T cells.
3. To determine the efficacy of IL-7/IL-15 programmed CD19.CAR-T cells in treating patients with CD19-positive lymphoma

Secondary Objectives

1. 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
2. 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
3. To assess the dynamics of intratumoral infiltration of CD19.CAR-T cells.
4. To correlate the subsets and differentiation of CD19.CAR-T cells to observed anti-tumor efficacy

Inclusion Criteria:

1. 18 Years to 70 Years, Male and female;

2. Expected survival > 12 weeks;

3. Performance score 0-2;

4. Histologically confirmed as CD19-positive lymphoma 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

5. Creatinine < 2.5 mg/dl;

6. ALT/AST < 3x normal;

7. Bilirubin < 2.0 mg/dl;

8. Adequate venous access for apheresis, and no other contraindications for leukapheresis;

9. Take contraceptive measures before recruit to this trial;

10. Written voluntary informed consent is given.

Exclusion Criteria:

1. Patients with symptoms of central nervous system
2. Accompanied by other malignant tumor
3. Active hepatitis B or C, HIV infection
4. Any other diseases could affect the outcome of this trial
5. Suffering severe cardiovascular or respiratory disease
6. Poorly controlled hypertension
7. A history of mental illness and poorly controlled
8. Taking immunosuppressive agents within 1 week due to organ transplantation or other disease which need long-lasting administration
9. Occurrence of unstable pulmonary embolism, deep vein thrombosis, or other major arterial/venous thromboembolic events 30 days prior to assignment
10. Reaching a steady dose if receiving anticoagulant therapy before assignment
11. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
12. Pregnant or lactating women
13. Subject suffering disease affects the understanding of informed consent or comply with study protocol.