Vereinte Kraft gegen Krebsstammzellen des Pankreaskarzinoms durch TRAIL-Lymphozyten und EpCAMxCD3 bispezifische Antikörper

Zusammenfassung

Obwohl Bauchspeicheldrüsenkrebs mit zu den aggressivsten Tumorerkrankungen zählt, gibt es bis heute keine zufriedenstellenden Therapieoptionen. Jüngste experimentelle Daten einer neuen Gen-Immuntherapie, die TRAIL-Lymphozyten und den bispezifischen Antikörper EpCAMxCD3 beinhaltet, sind vielversprechend. Der Todesligand TRAIL eliminiert selektiv Tumorzellen, während EpCAMxCD3 zytotoxische T-Lymphozyten gezielt zu Tumorzellen hinleitet. In der hier vorgestellten neuen Kombinationstherapie wurde TRAIL Protein durch ex vivo Manipulation verstärkt an die Oberfläche von zytotoxischen T-Lymphozyten gebracht. Gekoppelt an EpCAMxCD3 wurden diese auf Tumorzellen gelenkt, wo effektiv Apoptose durch den kombinierten zytotoxischen Effekt von Lymphozyten und TRAIL induziert wurde. Zudem bewirkte EpCAMxCD3 über eine verlängerte Kontaktzeit und eine erhöhte Affinität zwischen Lymphozyten und Tumorzellen die weitere Verstärkung des Zelltods. Diese Gen-Immuntherapie stimuliert die körpereigene Immunantwort und wirkt dadurch selbst gegen die hoch resistenten Krebsstammzellen, welche als Ursache des Tumorwachstums und der Metastasierung angesehen werden.

Summary

Although pancreatic cancer represents one of the most aggressive malignancies, there are no satisfying therapeutic options available. Recent experimental data with a gen-immunotherapy combining TRAIL-lymphocytes and bispecific antibody EpCAMxCD3 appear promising. The death ligand TRAIL selectively kills cancer cells, while bispecific antibody (bsAb) EpCAMxCD3 targets effector lymphocytes to cancer cells. In the new gene-immunotherapy presented here, increased levels of TRAIL protein were expressed on the cell surface of cytotoxic T-lymphocytes by ex vivo manipulation. Armed with bsAb EpCAMxCD3, TRAIL-lymphocytes were guided to tumor cells where enforced apoptosis was induced by combined cytotoxic effects of lymphocytes and TRAIL. In addition, EpCAMxCD3 further increased apoptosis by enhancing contact time and affinity between lymphocytes and tumor cells. This new gene-immunotherapy boosts endogenous immune responses and thereby even eliminates the highly resistant tumor stem cells, which are regarded as the major cause of tumor growth and metastasis.

Schlüsselwörter

Immuntherapie - Gentherapie - Tumorstammzellen - Pankreaskarzinom - Bispezifische Antikörper - TRAIL - Apoptose

Keywords

Immunotherapy - Gene therapy - Tumor stem cells - Pancreatic Cancer - Bispecific Antibodies - TRAIL - Apoptosis

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