CAR T Cell Receptor Immunotherapy for Patients With B-cell Lymphoma
Condition: Primary Mediastinal B-cell Lymphoma; Diffuse, Large B-cell Lymphoma; Diffuse Large B-Cell Lymphoma Transformed From Follicular Lymphoma; Mantle Cell
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for
      treating patients with B cell lymphomas or leukemias that involves taking white blood cells
      from the patient, growing them in the laboratory in large numbers, genetically modifying
      these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and
      then giving the cells back to the patient. This type of therapy is called gene transfer. In
      this protocol, we are modifying the patient s white blood cells with a retrovirus that has
      the gene for anti-cluster of differentiation 19 (CD19) incorporated in the retrovirus.

      Objective:

      The purpose of this study is to determine a safe number of these cells to infuse and to see
      if these particular tumor-fighting cells (anti-CD19 cells) cause tumors to shrink.

      Eligibility:

      - Adults age 18-70 with B cell lymphomas or leukemias expressing the CD19 molecule.

      Design:

      Work up stage: Patients will be seen as an outpatient at the National Institutes of Health
      (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab
      tests, and other tests as needed

      Leukapheresis: If the patients meet all of the requirements for the study they will undergo
      leukapheresis to obtain white blood cells to make the anti-CD19 cells. Leukapheresis is a
      common procedure, which removes only the white blood cells from the patient.

      Treatment: Once their cells have grown, the patients will be admitted to the hospital for the
      conditioning chemotherapy and the anti-CD19 cells. They will stay in the hospital for about 4
      weeks for the treatment.

      Follow up: Patients will return to the clinic for a physical exam, review of side effects,
      lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1
      year as long as their tumors are shrinking. Follow up visits will take up to 2 days.
    

Detailed description: 
      BACKGROUND:

        -  We have constructed a retroviral vector that encodes an anti-cluster of differentiation
           19 (CD19) chimeric antigen receptor (CAR) that recognizes the CD19 antigen. This
           chimeric receptor also contains the signaling domains of cluster of differentiation 28
           (CD28) and cluster of differentiation 3 (CD3)-zeta. The retroviral vector can be used to
           mediate genetic transfer of this CAR to T cells with high efficiency (> 50%) without the
           need to perform any selection.

        -  In co-cultures with CD19-expressing target cells, anti-CD19-CAR-transduced T-cells
           secreted significant amounts of interferon gamma (IFN-y) and interleukin 2 (IL-2).

        -  We have developed a process for cryopreserving the cell product which may lead to the
           ability for this product to be manufactured at a central location and shipped to other
           institutions for treatment of a broader patient population

      OBJECTIVE:

      - Primary objective:

      --With the approval of amendment S, to determine the safety and feasibility of the
      administration of cryopreserved anti-CD19-CAR engineered peripheral blood lymphocytes with a
      non-myeloablative conditioning regimen in patients with Bcell lymphomas.

      ELIGIBILITY:

      Patients of 18 years of age or older must:

        -  Have a CD19-expressing B-cell lymphoma

        -  Be a non-responder to, or recurred after one or more standard chemotherapy-containing
           regimens for their malignancy

        -  Currently require treatment due to progressive malignancy

        -  Be deemed to be incurable by standard therapy

      Patients may not have:

        -  A history of allogeneic stem cell transplantation

        -  Central nervous system (CNS) disease

      DESIGN:

        -  Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis (approximately 5.0x
           10^9 cells) will be cultured in the presence of anti-CD3 (muromonab-CD3 (OKT3)) and
           aldesleukin in order to stimulate T-cell proliferation.

        -  Transduction is initiated by exposure of approximately 1.0x 10^8 to 5.0x 10^8 cells to
           retroviral vector supernatant containing the anti-CD19 CAR.

        -  With the approval of Amendment S, patients will receive fludarabine and cyclophosphamide
           chemotherapy (NMA) for lymphodepletion, followed by cryopreserved
           anti-CD19-CAR-transduced T-cells.

        -  Patients will be followed until disease progression.

        -  Patients who have responded to treatment and then progress may receive one retreatment.
    

Intervention name(s): Fludarabine; Cyclophosphamide; Anti-cluster of differentiation 19 (CD19)-CAR PBL; Aldesleukin; Fludarabine; Cyclophosphamide
Intervention type(s): Drug; Drug; Biological; Drug; Drug; Drug
Intervention description(s): Days -5 to -1 (after administration of cyclophosphamide): 25 mg/m^2 intravenous (IV) over 30 minutes; Days -5 to -4: 60mg/kg intravenous (IV) over 60 minutes; Anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) peripheral blood lymphocytes ( PBL).
Day 0 (two to four days after the last dose of fludarabine); Cells will be infused via intravenous (IV) on the Patient Care Unit over 20-30 minutes.; Day 0: 720,000 IU/kg intravenously (IV) every 8 hours for a maximum of 15 doses.; Days -5 to -3 (after administration of cyclophosphamide): 30 mg/m^2 intravenous (IV) over 30 minutes; Days -5 to -3: 300mg/m^2 intravenous (IV) over 60 minutes
Other intervention name(s): Fludara; Cytoxan; Interleukin-2; IL-2; Fludara; Cytoxan
Intervention MeSH terms: Vidarabine; Aldesleukin; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Interleukin-2
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: B Cell Malignancies; T Cell Persistence; Immunotherapy; Cell Transfer; Leukemia; Chronic Lymphocytic Leukemia; CLL; Lymphoma