CLINICAL TRIAL: ADMINISTRATION OF PERIPHERAL BLOOD T-CELLS AND EBV SPECIFIC CTLS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary Objective To evaluate the safety of escalating doses of 14g2a.zeta chimeric receptor transduced autologous EBV specific cytotoxic T-lymphocytes (EBV-CTL)and 14g2a.zeta transduced autologous peripheral blood T-cells administered to patients with Neuroblastoma who have been lymphodepleted by CD45 monoclonal antibodies (MAbs). Secondary Objectives To determine the differential survival and function of these two infused cell-types in vivo, in particular to determine if chimeric receptor transduced EBV-CTLs survive longer than transduced peripheral-blood T-cells. To determine anti-tumor effects of transduced peripheral blood T-cells and EBV specific CTLs in vivo. The concept of exploiting the immune system to eradicate disease has had a long currency in neuroblastoma research, supported by many aspects of the tumor's biologic behavior, including spontaneous regression in younger children. In addition, because neuroblastoma is derived from embryonic neuroectoderm, it expresses antigens not widely detected in non-embryonic tissues11, and may overexpress other cellular antigens. Finally, in animals and in man, neuroblastoma cells are susceptible to cytotoxic effector mechanisms both in vitro and in vivo.13-15 Clinical immunotherapy for neuroblastoma has taken many forms which may be loosely classified into vaccine / cytokine approaches or the use of therapeutic monoclonal antibodies. By measuring the level of the transgene in peripheral blood we will be able to estimate the overall kinetics of gene- modified T-cell survival and determine whether expansion or persistence occures in vivo. Even if CTL derived signal does persist it is possible that the transgene-positive cells we detect will have lost one or other of their specificities for EBV and neuroblastoma. We will be able to use FACS sorting of tetramer positive cells to discover whether or not they retain their bifunctional activity against malignant and EBV-infected target cells.