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The fully synthetic glycopeptide MAG-Tn3 therapeutic vaccine induces tumor-specific cytotoxic antibodies in breast cancer patients

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Abstract

Cancer is one of the main causes of mortality worldwide and a major public health concern. Among various strategies, therapeutic vaccines have been developed to stimulate anti-tumoral immune responses. However, in spite of extensive studies, this approach suffers from a lack of efficacy. Recently, we designed the MAG-Tn3 vaccine, aiming to induce antibody responses against Tn, a tumor-associated carbohydrate antigen. The Tn antigen is of interest because it is expressed by several adenocarcinomas, but not normal cells. The fully synthetic glycopeptide vaccine MAG-Tn3 is composed of four arms built on three adjacent Tn moieties associated with the tetanus toxin-derived peptide TT830–844 CD4+ T-cell epitope. This promiscuous CD4+ T-cell epitope can bind to a wide range of HLA–DRB molecules and is thus expected to activate CD4+ T-cell responses in a large part of the human population. The MAG-Tn3 vaccine was formulated with the GSK-proprietary immunostimulant AS15, composed of CpG7909, MPL, and QS21, which has been shown to stimulate both innate and humoral responses, in addition to being well tolerated. Here, seven patients with localized breast cancer with a high-risk of relapse were immunized with the MAG-Tn3 vaccine formulated with AS15. The first results of phase I clinical trial demonstrated that all vaccinated patients developed high levels of Tn-specific antibodies. Moreover, these antibodies specifically recognized Tn-expressing human tumor cells and killed them through a complement-dependent cytotoxicity mechanism. Overall, this study establishes, for the first time, the capacity of a fully synthetic glycopeptide cancer vaccine to induce specific immune responses in humans.

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Acknowledgements

We thank Jamila Louahed (GSK Vaccines) for her continuous support, helpful discussions and critical review of the publication and the clinical protocol. We thank the CB UTechS platform and the molecular biophysics facility (especially Sylviane Hoos) for their support and help with the various devices and Luisa Nardini, Natalia Zmarlak, Ferdinand Nanfack Minkeu, and Inge Holm for sharing equipment. We thank Eleonore De Guillebon from the Hôpital Européen Georges Pompidou and Thomas Bachelot from the Centre Hospitalier Léon Bérard for their valuable support in the organization of this clinical trial. We thank the hospital staff for their daily work on the project and the patients for their agreement to participate in the trial.

Funding

The work was funded by the donors of the MAG-Tn3 program. GlaxoSmithKline Biological SA provided AS15 and preparing the final formulation of the MAG/AS15 vaccine.

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Authors and Affiliations

  1. Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, 28 rue du Dr Roux, 75015, Paris, France

    Pierre Rosenbaum & Claude Leclerc

  2. INSERM U1041, 75015, Paris, France

    Pierre Rosenbaum & Claude Leclerc

  3. Institut Pasteur, Centre de Recherche Translationnelle-Coordination Clinique, 75015, Paris, France

    Cécile Artaud

  4. Institut Pasteur, Unité de Chimie des Biomolécules, 75015, Paris, France

    Sylvie Bay & Christelle Ganneau

  5. Centre National de la Recherche Scientifique UMR3523, 75015, Paris, France

    Sylvie Bay & Christelle Ganneau

  6. Institut de Cancérologie de l’Ouest, Saint-Herblain, 44800, Nantes, France

    Mario Campone, Carole Gourmelon & François Pein

  7. Institut Gustave Roussy, 94800, Villejuif, France

    Suzette Delaloge & Andrea Varga

  8. Département d’Oncologie Médicale, Institut Curie, 75015, Paris, France

    Delphine Loirat & Marie-Paule Sablin

  9. Assistance Publique-Hôpitaux de Paris (AP-HP), Centre d’Essais Précoces en Cancérologie, Hôpital Européen Georges-Pompidou, Faculté de Médecine Paris Descartes, 75015, Paris, France

    Jacques Medioni

  10. Medical Oncology Department, Centre Léon Bérard, 69008, Lyon, France

    Olivier Tredan

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  1. Pierre Rosenbaum
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Contributions

CL conceived and supervised the study, discussed the data, and wrote the manuscript. PR designed and performed the experiments analyzed the results and wrote the manuscript. CA coordinated the clinical trial, participated in the collection of the clinical data, and provided input for the manuscript. SB developed the process of vaccine synthesis and provided input for the manuscript. CG prepared the Tn3 antigen used in the ELISA. MC (investigator coordinator), SD, JM, CG, DL, FP, M-PS, OT, and AV designed and performed oversight of the clinical trial.

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Correspondence to Claude Leclerc.

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Rosenbaum, P., Artaud, C., Bay, S. et al. The fully synthetic glycopeptide MAG-Tn3 therapeutic vaccine induces tumor-specific cytotoxic antibodies in breast cancer patients. Cancer Immunol Immunother 69, 703–716 (2020). https://doi.org/10.1007/s00262-020-02503-0

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