GD2 ganglioside-specific immunotherapy of cancer
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Immunotherapy has been pursued for over a century in an attempt to defeat cancer. Over the last decade, tumor associated antigens have been identified and tumor-specific monoclonal antibodies (mAbs) have emerged as effective and specific immunotherapeutics against human cancers. In particular, carbohydrate antigens that are over-expressed on the surface of malignant cells are typically perceived as attractive targets. One of such antigens is GD2 ganglioside which is abundantly expressed on the surface of neuroectodermally-derived tumor cells, whereas on normal cells its presence is restricted to neurons, peripheral pain fibers, and skin melanocytes. However, gangliosides are weakly immunogenic and are considered inadequate for generating tumor-specific cellular responses. Therefore, trials have been undertaken in order to develop more potent surrogate antigens. These approaches include production of anti-idiotypic antibodies or screening of phage display peptide libraries with anti-carbohydrate antibodies in order to isolate immunogenic peptide mimics. In my experimental work, GD2-specific monoclonal mAbs 14G2a, 3F8, and ME36.1 were used to screen the LX8 and X 15 phage display peptide library expressing conformational and linear peptides, respectively. This approach led to isolation of non-overlapping peptides that exhibited mimicry with GD2 ganglioside, based on their abilities to inhibit the binding of GD2-specific mAbs to GD2-positive tumor cells. Immunization of mice with the mimetic peptides expressed in DNA plasmid or conjugated with keyhole limpet hemocyanin (KLH) protein carrier were effective in inducing GD2-specific IgM and IgG antibody responses. The vaccine-induced antibodies were capable of mediating complement-dependent cytotoxicity (CDC) and exhibited protection against subcutaneous (s.c.) human GD2-positive melanoma growth in the SCID mouse xenograft model. We have also observed a direct inhibitory effect of GD2-specific mAbs on the growth of GD2 + tumor cells in vitro which was associated with the ability of these antibodies to induce apoptosis of tumor cells through caspase-dependent and caspase-independent mechanisms. In conclusion, the presented data suggest that (i) inter-conversion of weakly immunogenic GD2 ganglioside into peptide mimics leads to the breaking of tolerance in the immunized animals and therefore might be useful in active, specific immunotherapy against GD2-positive tumors, and (ii) multiple apoptotic pathways can be triggered by GD2-specific mAbs in GD2 + tumor cells.