A Phase I/IIa Trial for the Treatment of Relapsed or Chemotherapy-Refractory CLL and Indolent B Cell Lymphoma Using Autologous T Cells Genetically Targeted to the B Cell-Specific Antigen CD19
Background and Rationale
We have developed a novel immunotherapy based on the genetic modification of patient T cells to recognize the B cell-specific antigen CD19. T cells can be genetically modified with a replication defective retroviral vector containing a gene encoding a chimeric antigen receptor (CAR) specific for the CD19 antigen. A chimeric antigen receptor is composed of a single chain variable fragment derived from a monoclonal antibody fused to the signal transduction components of a T cell receptor, thus combining the targeted antigen specificity of an antibody with the cytotoxic antitumor effects of T cells. Furthermore, this novel approach allows for the rapid generation of tumor-targeted T cells, overcomes the obstacle of identifying a suitable HLA-matched donor, and eliminates the risk of graft-versus-host disease.
We have previously demonstrated in mice that adoptive T cell therapy using these genetically modified T cells targeted to CD19 can effectively eradicate systemic B cell tumors. Based on this exciting preclinical data, we are currently conducting a phase I clinical trial for patients with relapsed or chemotherapy-refractory CLL and indolent B cell lymphomas. To date, the treatment has been demonstrated to be safe with evidence of promising clinical activity.
Eligibility
- Patients with persistent or relapsed CLL
- Patients with persistent or relapsed indolent B cell lymphomas, including small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and Waldenström macroglobulinemia
- Creatinine ≤ 2.0, bilirubin ≤ 2.0, AST/ALT ≤ 3x normal, PT/PTT ≤ 2x normal outside the setting of stable chronic anticoagulation therapy, granulocytes ≥ 1,000, platelets ≥ 50,000, hemoglobin ≥ 8.0
- Adequate cardiac function (LVEF ≥ 40%) as assessed by Echo or MUGA scan
- Life expectancy of > 3 months
- Patients who have received prior allogeneic bone marrow transplant are not eligible for this study
Study Objective
- To determine the safety and maximum tolerated dose (MTD) of modified T cells
- To assess the antitumor efficacy of modified T cell therapy
Study Design
Eligible patients will initially undergo a leukapheresis procedure to obtain autologous T cells. Isolated T cells will be genetically modified to target CD19 and expanded within the Center for Cell Engineering at Memorial Sloan-Kettering. Once a sufficient number of gene-modified T cells are obtained, patients will be admitted to Memorial Hospital to receive lympho-depleting cyclophosphamide chemotherapy followed by modified T cell infusion. Patients will be monitored closely for at least 48 hours following T cell infusion and will be discharged if no adverse events occur. Serial sampling of blood and bone marrow will be performed following treatment to assess toxicity, therapeutic effects, and survival of the genetically modified T cells.
Contact
For more information and to find out whether a patient is eligible for this study, please contact Dr. Renier Brentjens at 212-639-7053. Patients who respond to the therapy will be returned to your care approximately three months after T cell therapy.
