Anti-NeuGcGM3 Antibodies, Actively Elicited by Idiotypic Vaccination in Nonsmall Cell Lung Cancer Patients, Induce Tumor Cell Death by an Oncosis-Like Mechanism

Department of Antibody Engineering, Center of Molecular Immunology, Havana 11600, Cuba.
The Journal of Immunology (Impact Factor: 4.92). 02/2011; 186(6):3735-44. DOI: 10.4049/jimmunol.1000609
Source: PubMed


1E10 is a murine anti-idiotypic mAb specific for an idiotypic mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In melanoma, breast, and lung cancer patients, this anti-idiotypic Ab was able to induce a specific Ab response against N-glycosylated gangliosides, attractive targets for cancer immunotherapy as these glycolipids are not naturally expressed in humans. A clinical study with nonsmall cell lung cancer patients showed encouraging clinical benefits. Immunological studies performed in 20 of these patients suggested a correlation between the induction of Abs against NeuGcGM3 and longer survival times. The induced anti-NeuGcGM3 Abs recognized and directly killed tumor cells expressing the Ag, by a mechanism independent of complement activation. In the present work, we show that this cytotoxicity differs from apoptosis because it is temperature independent, no chromatin condensation or caspase 3 induction are detected, and the DNA fragmentation induced has a different pattern than the one characteristic for apoptosis. It is a very quick process and involves cytosqeleton reorganization. The Abs induce cellular swelling and the formation of big membrane lesions that allow the leakage of cytoplasm and the loss of the cell membrane integrity. All of these characteristics resemble a process of oncotic necrosis. To our knowledge, this is the first report of the active induction in cancer patients of NeuGcGM3-specific Abs able to induce complement independent oncotic necrosis to tumor cells. These results contribute to reinforcing the therapeutic potential of anti-idiotypic vaccines and the importance of NeuGcGM3 ganglioside as antitumor target.

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Available from: Rolando Pérez
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    • "Each of these anti-idiotypes seems to have a different mechanism of action against cancer cells but parallel mechanisms observed with CMPs. In the case of the anti-idiotype that mimics NGc gangliosides it generates a humoral response that triggers cell death but differently than typical apoptosis (113). Patients that developed IgG and/or IgM Abs against NeuGcGM3 showed longer median survival times (114). "
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    • "On the other hand, it was shown that antibodies to tumor-associated ganglioside NeuGcGM3 induced cell death by mechanism of necrosis with formation of the membrane pores. The researchers showed that this process is caspase-independent [24,36]. Such results could be explained by both the different origin of tumor cell lines used in these studies, and by targeting different tumor-associated gangliosides. "
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    • "Despite that pathogen-associated animal models were often used to validate vaccination with anti-Ids, anti-Id vaccination has made it to the clinic for cancer. A number of monoclonal antibodies that mimic distinct human tumor-associated antigens as well as Id vaccines have demonstrated encouraging results in clinical studies for solid tumors (; Maruyama et al., 2000; Ruffini et al., 2005; Lee et al., 2007; Neninger et al., 2007; Fernandez et al., 2010; Hernandez et al., 2011; Ng et al., 2012). While the theoretical hypothesis is sound, trials have been limited and have not been tested prospectively. "
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