Genetically Engineered Lymphocyte Therapy in Treating Patients With B-Cell Leukemia or Lymphoma That is Resistant or Refractory to Chemotherapy

• New onset secondary malignancies [ Designated as safety issue: No ]
• Occurrence of study related adverse events (defined as >= Grade 3 signs/symptoms, laboratory toxicities, and clinical events) that are possibly, likely, or definitely related to study treatment [ Time Frame: Until week 24 ] [ Designated as safety issue: Yes ]
• Feasibility to manufacture CART-19 cells from patient apheresis products [ Designated as safety issue: No ]
• Engraftment as defined by duration of in vivo survival of CART-19 cells [ Designated as safety issue: No ]

• Anti-tumor responses to CART-19 cell infusions [ Designated as safety issue: No ]
• Overall survival and cause of death [ Designated as safety issue: No ]
• Correlation of in vitro killing assays of CART-19 cells against patient tumor with clinical response in patients with stored or accessible tumor cells [ Designated as safety issue: No ]
• Host immunity against the murine anti-CD19 or other elements of the transgene or vector such as VSV-G, and correlation with loss of detectable CART-19 (loss of engraftment) [ Designated as safety issue: No ]
• General anti-tumor immunity [ Time Frame: Baseline and post-infusion ] [ Designated as safety issue: No ]
• Relative survival of CART-19 TCR zeta and TCR zeta:4-1BB cells over time (in subjects infused with mixture of T cells) [ Designated as safety issue: No ]
• Relative subsets of CART-19 T cells (Tcm, Tem, and Treg) [ Designated as safety issue: No ]
• Relative engraftment of CART-19 cells expressing TCR zeta or TCR zeta:4-1BB domains [ Designated as safety issue: No ]

Adoptive immunotherapy has been successful in treatment of cancer due the graft versus tumor effect, but effective treatment is typically associated with graft versus host disease (GVHD). Autologous T cell transfer for cancer immunotherapy is an alternative approach that offers cancer specific immunotherapy without GVHD. To break immunological tolerance to tumors, autologous T cells have been modified with tumor-specific T cell receptors (TCRs)1,2. Studies using this approach have demonstrated the potent expansion, trafficking and antitumor activity of the redirected autologous T cells, but the approach is limited by MHC restriction and therefore is challenging for broad clinical application3,4. An alternative approach is to modify T cells with a chimeric immunoreceptor (CIR) which mimics the signaling of the natural TCR when encountering tumor antigen. This creates a universal tumor specific TCR that can be used across patients with a common tumor antigen5. Despite advances in current treatments, most patients with B cell malignancies remain incurable. Most B cell lymphomas, mantle cell lymphomas, ALLs, CLLs, hairy cell leukemias, and a subset of acute myelogenous leukemias express the CD19 antigen6-8. Expression of CD19 is highly restricted to B cells, and is not detected on other normal tissues, including hematopoietic stem cells, thus making it a safe tumor antigen for the CIR approach9. Previous clinical approaches have utilized the CD3 or Fc receptor signaling chain for T cell activation10. Costimulation via 4-1BB signaling has been shown to improve antitumor activity in vitro, and therefore incorporation of this signaling chain in the CIR may improve function of the T-bodies in vivo11-13. Our hypothesis is that CD19:4-1BB:CD3 modified cells will demonstrate improved engraftment and function over CD19-CD3 modified cells in patients with B cell malignancies.

Primary objectives:

1. To evaluate the safety and feasibility of a single target dose of 5 times 10e9 total cells, acceptable range of 1.5 times 10e7 to 5 times 10e9 total cells comprised of autologous CART-19 cells that express the TCR zeta and 4-1 BB costimulatory domain.

Secondary objectives:

1. Proof of mechanism: determine if 2nd generation CAR expressing 4-1BB costimulation domains have improved persistence in patients.
2. Proof of concept: determine the effects of CART-19 on CD19 expression in vivo.
3. Proof of bioactivity: Evaluate changes in systemic soluble immune factors in patients
4. Proof of bioactivity: Evaluate impact of CART19 treatment on tumor burden
5. Explore whether CART-19 cells retain anti-tumor activity in vivo.
6. Determine if host immunity develops against CART-19.
7. Characterize the relative subsets of CART-19 T cells (Tcm, Tem, and Treg).
8. Describe survival and response rates

• Hematopoietic/Lymphoid Cancer
• Adult Acute Lymphoblastic Leukemia in Remission
• B-cell Adult Acute Lymphoblastic Leukemia
• B-cell Chronic Lymphocytic Leukemia
• Prolymphocytic 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

• Other: laboratory biomarker analysis
• Genetic: polymerase chain reaction
  Other Name: PCR
• Genetic: reverse transcriptase-polymerase chain reaction
  Other Name: RT-PCR
• Biological: anti-CD19-CAR retroviral vector-transduced autologous T cells
  Given IV
• Biological: genetically engineered lymphocyte therapy

Inclusion

• Male and female subjects with CD19+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to < 2 year survival) with currently available therapies will be enrolled
• CD19+ leukemia or lymphoma
• ALL in CR2 or CR3 and not eligible for allogeneic SCT because of age, comorbid disease, or lack of available family member or unrelated donor
• Follicular lymphoma, previously identified as CD19+:
• At least 2 prior combination chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy
• Stage III-IV disease
• Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval < 1 year)
• Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc)
• CLL:
• At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior
• Less than 2 years between last chemotherapy and progression (i.e. most recent progression free interval < 2 years)
• Not eligible or appropriate for conventional allogeneic SCT
• Patients who achieve only a partial response to FCR as initial therapy will be eligible.
• Mantle cell lymphoma:
• Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT
• Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc...)
• Relapsed after prior autologous SCT
• B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT
• Diffuse large cell lymphoma, previously identified as CD19+:
• Residual disease after primary therapy and not eligible for autologous SCT
• Relapsed after prior autologous SCT
• Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate of conventional allogeneic or autologous SCT
• Expected survival > 12 weeks
• Creatinine < 2.5 mg/dl
• ALT/AST < 3x normal
• Bilirubin < 2.0 mg/dl
• Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy
• Adequate venous access for apheresis, and no other contraindications for leukapheresis
• Voluntary informed consent is given

Exclusion

• Pregnant or lactating women
• The safety of this therapy on unborn children is not known
• Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
• Uncontrolled active infection
• Active hepatitis B or hepatitis C infection
• Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary
• Previously treatment with any gene therapy products
• Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to CD3/CD28 costimulation
• Any uncontrolled active medical disorder that would preclude participation as outlined
• HIV infection