53. Preliminary Results of a Pilot Phase I Clinical Trial of Adoptive Immunotherapy for B Cell Lymphoma Using CD8+ T Cells Genetically Modified To Express a Chimeric T Cell Receptor Recognizing CD20

Abstract

Follicular Lymphoma (FL) is the second most common type of Non-Hodgkin's Lymphoma (NHL) in the United States, with over 120,000 Americans living with the disease. FL is considered incurable with conventional therapies and innovative new approaches are needed. We have initiated a pilot Phase I clinical trial to test the feasibility, safety, toxicity, and efficacy of treating patients with relapsed indolent B cell lymphomas with autologous CD8+ cytotoxic T lymphocytes (CTL) that have been genetically modified to express a chimeric T cell receptor (cTCR) recognizing the CD20 antigen present on B cell lymphomas. Five patients have been registered to the protocol to date. Peripheral blood mononuclear cells were obtained from patients by apheresis, activated with anti-CD3 monoclonal antibody and interleukin 2 and transfected by electroporation with a plasmid encoding a CD20-specific scFvFc:zeta chimeric immunoreceptor as well as a neomycin-resistance selection gene. Transfectants were selected using G418, and cloned by limiting dilution. CD8+ clones expressing the cTCR and manifesting CD20-specific cytotoxicity were identified by flow cytometry and chromium-51 cytotoxicity assays. Selected clones were expanded and infused into two of the patients at escalating doses (108, 109, and 3.3 |[times]| 109 cells/m2) on three occasions over a period of 10 days. Two additional patients are scheduled for T cell infusions in the near future. One patient is now off study because the clones failed to expand sufficiently to numbers required for therapy. No significant toxicities attributable to the T cell infusions were observed. There have been no cellular or humoral immune responses to the genetically modified T cells in the two treated patients. T cells expressing the cTCR were detectable in the peripheral blood of patients by PCR for 14 days after infusions. One patient was maintained in complete remission for over a year after T cell infusions, and a second patient was maintained in a partial remission for four months. Future planned interventions include infusion of polyclonal populations of transfected CD4 helper T cells with cytotoxic CD8 T cells rather than CD8 clones, subcutaneous administration of low dose interleukin 2, and introduction of a modified plasmid containing CD28 and CD137 co-stimulatory domains in addition to the CD3 zeta chain.