Adoptive Therapy Using Autologous Cytotoxic Lymphocytes

In vitro expansion of tumor-reactive T cells,followed by their in vivo re-infusion, is an effective approach in several murine models; however, this approach remains complex for clinical translation,particularly in smaller pediatric patients where obtaining adequate numbers of autologous T cells for in vitro expansion remains somewhat problematic. This method does allow in vitro manipulation of the T cells prior to their re-infusion. One manipulation is to use bispe-cific antibodies (see section to target T cells more efficiently. Although successful in preclinical models, clinical efficacy has been difficult to achieve partly because of insufficient cell dose, inefficient homing, and poor survival in vivo. Another development is to transfect these T cells with cell surface Fab or scFv chimerized with cytoplasmic activation (e.g., CD3Ç or g chain) or survival (CD28) proteins. While the antibody fragment provides tumor recognition, the signaling domains activate downstream pathways for optimal T-cell activation (Cheung et al. 2003; Rossig et al. 2001). Since these genetically modified T-cells are not restricted by MHC and can be expanded in vitro, they are potentially useful for adoptive therapy of NB (Cheung et al. 2003; Rossig et al. 2001). An alternative approach grafts the Fab recognition components of the tumor-reactive antibody directly to the TCR alpha and beta receptors to enable signal transmission directly through the intact TCR. Both of these approaches have shown success in pre-clinical models and scFv-CIR directed to least three antigen systems [L1CAM; (Jensen et al., unpublished data); GD2 (Rossig et al. 2001); gp58 (Cheung et al. 2003)] are under investigation in NB.

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