Zusammenfassung
Hintergrund
Tumoren können vom Immunsystem erkannt werden. Physiologische Mechanismen der immunologischen Toleranz und Ignoranz führen jedoch dazu, dass Tumoren trotzdem nicht abgestoßen werden. Der Weg von der Induktion einer Immunantwort bis zu einer Abstoßungsreaktion ist komplex und störanfällig, bildhaft dargestellt im Krebsimmunzyklus von Chen und Mellman.
Ergebnisse
Mit kontinuierlich verbesserter Methodik wurde eine Vielzahl von Antigenen unterschiedlicher Expressionsmuster identifiziert, die sich als Zielstrukturen für die Krebsimmuntherapie eignen. Es ist jetzt möglich, individuelle mutierte Neoantigene mit vertretbarem Aufwand zu identifizieren. Die therapeutische Impfung zielt ebenso wie die Checkpointblockade auf die Rekrutierung körpereigener Abwehrmechanismen. Die unzulänglichen Ergebnisse bisheriger Impfstudien werden v. a. damit erklärt, dass diese weder die Individualität der Tumor-Wirt-Interaktion noch immunologische Gegenregulation und die Durchbrechung tumoreigener Immunbarrieren in ausreichendem Maße beinhalteten. Die klinischen Erfolge der Checkpointblockade unterstreichen − wenn auch nur bei einer Subgruppe von Patienten mit nachhaltigem Effekt − das im körpereigenen Immunrepertoire liegende Potenzial.
Schlussfolgerungen
Technologische Fortschritte und eine enge Verzahnung von grundlagen- und anwendungsorientierter Forschung haben nahezu exponentiell wachsende Optionen für die Entwicklung neuer Immuntherapeutika geschaffen. Um dies nachhaltig und breit nutzen, ist es essenziell, immunologisch relevante prädiktive Biomarker zu entdecken und für den differenzierten Einsatz unterschiedlicher Immuntherapieverfahren und deren rationale Kombination auch mit nichtimmunologischen Therapien zu etablieren, um den Krebsimmunzyklus in Gang zu halten.
Abstract
Background
Tumors can be recognized by the immune system; however, physiological mechanisms of tolerance and ignorance regularly lead to tumors evading rejection. The way from induction of an immune response to final killing of cancer cells is complex and highly susceptible to failure, which is allegorized by the cancer immunity cycle described by Chen and Mellman.
Results
Continuous methodological progress has enabled the identification of a multitude of target antigens for cancer immunotherapy, with individual mutated neoantigens becoming increasingly popular. Therapeutic vaccination as well as checkpoint blockade aim at recruiting or enhancing anti-tumor responses from the patients’ own immune system. It is assumed that therapeutic vaccination has so far failed largely because the design of previous trials did not adequately consider the individuality of tumor/host interactions and did not include measures to circumvent counterregulation by the cellular immune system and to penetrate tumor immune barriers. This is supported by the clinical success of checkpoint blockade, which unequivocally demonstrates the potential of the patients’ immune repertoire, even though only a subset of patients experienced durable responses.
Conclusion
Continuous technical advancement and a close alliance between basic and applied research has generated almost exponentially growing options for the development of novel immunotherapeutic agents. To convert this into a permanent and broadly applicable clinical success, it will be of utmost importance to detect and establish immunologically relevant predictive biomarkers to guide the selective application of the different immunotherapy procedures and for evidence-based complementary combined approaches of any kind to keep the cancer immunity cycle moving.
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Dieser Beitrag wurde in der Zeitschrift Der Onkologe 2017 · 23:807–814, https://doi.org/10.1007/s00761-017-0270-2 erstveröffentlicht. Zweitpublikation mit freundlicher Genehmigung des Autors.
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Wölfel, T. Grundlagen der Krebsimmuntherapie. Wien klin Mag 21, 80–85 (2018). https://doi.org/10.1007/s00740-018-0221-6
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DOI: https://doi.org/10.1007/s00740-018-0221-6