Einsatz tumorassoziierter Antigene in der Immuntherapie und Immundiagnostik des Mammakarzinoms

Zusammenfassung

In den letzten Jahren sind zahlreiche Immuntherapien gegen maligne Erkrankungen entwickelt worden. Dies ist darauf zurückzuführen, dass durch die wesentlichen Verbesserungen zellulärer, biochemischer und molekularer Techniken Immunantworten auf humoraler und zellulärer Ebene detaillierter analysiert und verstanden werden konnten. So konnte vor allem die Charakterisierung zahlreicher tumorassoziierter Antigene, die als Zielstrukturen immunologischer Abwehrprozesse dienen können, erfolgen.

Da beim Mammakarzinom der Zusammenhang zwischen minimaler Resttumorerkrankung und erneutem Auftreten des Tumors erkannt wurde, ist ein wichtiger Aspekt bei der Entwicklung neuer ergänzender Therapiekonzepte die Nutzung immunologischer Abwehrprozesse. Dabei ist das Ziel die erfolgreiche systemische Aktivierung tumorspezifischer T-Lymphozyten und die Ausbildung eines immunologischen Gedächtnisses im Patienten. Die Fähigkeit spezifischer T-Zellen zur Zirkulation würde die Erkennung und Zerstörung von Metastasen und Mikrometastasen ermöglichen, die sich gängigen Therapiekonzepten wie der Chemo- und Radiotherapie entziehen. Auch wenn die Zukunft therapeutischer Vakzinierungen sicher in der Adjuvanz liegen wird, haben erste Erfahrungen bei Melanomen und Nierenzellkarzinomen gezeigt, dass auch Patienten mit relativ hoher Tumorlast von Immuninterventionen profitieren können.

Diese Übersicht soll Fortschritte und Möglichkeiten in der Entwicklung verschiedener Vakzinierungsstrategien und deren Verlaufskontrollen verdeutlichen, die sich zumindest teilweise die Kenntnis tumorassoziierter Antigene zu Nutze machen. Dazu zählt deren direkter Einsatz als Peptidvakzine oder deren Kombinationen mit Adjuvanzien und antigenpräsentierenden Zellen. Neben definierten Peptidantigenen wird auch der Tumor selbst häufig als Antigenquelle genutzt, die zwar das gesamte Antigenspektrum eines individuellen Tumors abdeckt, jedoch weitgehend undefiniert ist. Hier werden beispielsweise genetisch modifizierte Tumorzellvarianten eingesetzt, die in der Lage sind tumorspezifische immunologische Toleranz zu durchbrechen und so die Induktion einer Immunabwehr bewirken sollen.

Abstract

Recent advances in tumor immunology - such as the characterization of tumor-associated antigens recognized by cellular effectors of the immune system and the improved understanding of antigen processing and presentation - have opened new perspectives on cancer immunotherapy. The most important new approaches are peptide vaccines and whole-cell vaccines (tumor-cell-based or immune-cell-based). The advantage of tumor-cell-based vaccines is that they comprise the complete antigen pool of an individual tumor for activating polyclonal immune responses. The introduction of genes encoding costimulatory molecules or cytokines aims to confer their immunostimulatory potential. The rationale for fusing tumor cells and antigen-presenting cells is that the hybrid cell will display the antigenicity of the tumor and the immunogenicity of the fusion partner. Since the antigenic repertoire of tumor-cell-based vaccines is usually not fully characterized, it is difficult to estimate their immunostimulatory potential. To be able to assess vaccine-induced immune reactions and clinical responses it will be necessary to at least partially characterize the antgenicity of cellular vaccines and to define surrogate parameters.

The continuously increasing number of HLA-restricted tumor antigens - also identified in breast cancer - allowed the development of antigen-defined vaccines. Direct in vivo administration of peptides in combination with adjuvants suitable for establishing effective immune responses or ex vivo loading of dendritic cells with tumor-specific epitopes are target-specific immunation approaches. Cocktails of synthetic peptide epitopes should permit targeting multiple antigens while avoiding the development of antigen-loss variants.

Most clinical phase I/II trials to date indicate that cellular or peptide-based vaccines are safe. But the individual studies are heterogenous and based on small numbers of patients. This review describes advances in vaccination strategies and treatment approaches based on tumor-assocated antigens.

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