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Antibody-dependent cell-mediated cytotoxicity induced by active immunotherapy based on racotumomab in non-small cell lung cancer patients

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Abstract

Antitumor strategies based on positive modulation of the immune system currently represent therapeutic options with prominent acceptance for cancer patients’ treatment due to its selectivity and higher tolerance compared to chemotherapy. Racotumomab is an anti-idiotype (anti-Id) monoclonal antibody (mAb) directed to NeuGc-containing gangliosides such as NeuGcGM3, a widely reported tumor-specific neoantigen in many human cancers. Racotumomab has been approved in Latin American countries as an active immunotherapy for advanced non-small cell lung cancer (NSCLC) treatment. In this work, we evaluated the induction of Ab-dependent cell-mediated cytotoxicity (ADCC) in NSCLC patients included in a phase III clinical trial, in response to vaccination with racotumomab. The development of anti-NeuGcGM3 antibodies (Abs) in serum samples of immunized patients was first evaluated using the NeuGcGM3-expressing X63 cells, showing that racotumomab vaccination developed antigen-specific Abs that are able to recognize NeuGcGM3 expressed in tumor cell membranes. ADCC response against NeuGcGM3-expressing X63 (target) was observed in racotumomab-treated- but not in control group patients. When target cells were depleted of gangliosides by treatment with a glucosylceramide synthase inhibitor, we observed a significant reduction of the ADCC activity developed by sera from racotumomab-vaccinated patients, suggesting a target-specific response. Our data demonstrate that anti-NeuGcGM3 Abs induced by racotumomab vaccination are able to mediate an antigen-specific ADCC response against tumor cells in NSCLC patients.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

Anti-id:

Anti-idiotype

PDMP:

d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol

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Acknowledgements

The authors gratefully acknowledge Diego Mengual Gomez for his valuable support with the blood samples from healthy donors. The authors also thank Marina Pifano and Nazareno Gonzalez for their valuable contribution during the statistical analysis of the data. Valeria I Segatori and Héctor A Cuello are research fellows of ANPCyT (Argentina). Marina Albertó is a research fellow and Mariano R Gabri and Daniel F Alonso are members of the National Research Council (CONICET, Argentina).

Funding

This study was partially funded by National University of Quilmes (Grant No. 1398/15) and ELEA Laboratories.

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Authors and Affiliations

  1. Molecular Oncology Laboratory, National University of Quilmes, Roque Saenz Peña 352, Bernal, B1876BXD, Argentina

    Valeria I. Segatori, Héctor A. Cuello, Cynthia A. Gulino, Marina Albertó, Daniel F. Alonso & Mariano R. Gabri

  2. Institute of Immunology, Genetics and Metabolism (INIGEM), University of Buenos Aires, Avenida Córdoba 2351, Buenos Aires, C1120AAF, Argentina

    Cecilia Venier

  3. Elea Laboratories, Sanabria 2353, Buenos Aires, C1417AZE, Argentina

    Marcelo D. Guthmann & Ignacio A. Demarco

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  1. Valeria I. Segatori
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  2. Héctor A. Cuello
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  3. Cynthia A. Gulino
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  4. Marina Albertó
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  6. Marcelo D. Guthmann
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  8. Daniel F. Alonso
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  9. Mariano R. Gabri
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Contributions

Valeria I. Segatori and Mariano R. Gabri participated in the conception and design of the experiments, the analysis and interpretation of data and in the process of manuscript writing. Héctor A. Cuello, Cynthia A. Gulino and Marina Albertó also contributed to the final version of the manuscript. Valeria I. Segatori, Héctor A. Cuello, Cynthia A. Gulino and Marina Albertó worked in development of methodology and acquisition of data. Cecilia Venier was involved in the ELISA assays. Marcelo D. Guthmann and Ignacio A. Demarco were responsible for patients’ samples. Review of the manuscript was done by Daniel F. Alonso and Mariano R. Gabri.

Corresponding author

Correspondence to Mariano R. Gabri.

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Conflict of interest

Marcelo D. Guthmann and Ignacio A. Demarco are full employees of Elea Laboratories. They have no conflict of interest to declare. All other authors declare that they have no potential conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

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Segatori, V.I., Cuello, H.A., Gulino, C.A. et al. Antibody-dependent cell-mediated cytotoxicity induced by active immunotherapy based on racotumomab in non-small cell lung cancer patients. Cancer Immunol Immunother 67, 1285–1296 (2018). https://doi.org/10.1007/s00262-018-2188-y

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  • DOI: https://doi.org/10.1007/s00262-018-2188-y

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