Immunobiology and Gene-Based Immunotherapy of Hepatocellular Carcinoma

Zusammenfassung

Einleitung: Das hepatozelluläre Karzinom (HCC) ist einer der häufigsten Tumoren weltweit mit ca. 1 Million Neuerkrankungen pro Jahr. Die Resektion und Lebertransplantation sind die bisher einzigen potenziell kurativen Therapieansätze in ausgewählten Fällen. Lokalablative Verfahren sind komplikationsarm, aber häufig mit Lokalrezidiven, intrahepatischen Metastasen oder neuen HCC-Herden in der zirrhotischen Leber assoziiert. Deshalb sind neue therapeutische Ansätze gegen das HCC und ein verbessertes Verständnis der HCC-Immunbiologie von hoher Priorität. In diesem Artikel sollen neue molekulare Therapieansätze zur Behandlung des HCC und die dafür notwendigen immunpathogenetischen Zusammenhänge dargestellt werden. Material und Methoden: Eine systematische Medline-Literatursuche wurde in allen zitierten Sprachen ab 1970 durchgeführt. Ergebnisse: Eine Vielzahl spezifischer und unspezifischer immunstimulierender Strategien gegen das HCC wurde bisher in präklinischen experimentellen Modellen mit viel versprechenden Resultaten untersucht. Obwohl die bisherigen tumorimmuntherapeutischen Ansätze nur mäßigen klinischen Erfolg bei verschiedenen Tumorentitäten zeigten, konnten mittels neuer molekularer Methoden in den letzten Jahren neue Tumorantigene wie das α-Fetoprotein (AFP) identifiziert werden. Das verbesserte Verständnis der Tumorimmunbiologie ist der Grundstein für eine erfolgreiche Immuntherapie von Tumoren. Erste klinische Phase-I- und -II-Studien mit dem Ziel einer HCC-Immuntherapie unter Verwendung dendritischer Zellen als zelluläres Adjuvans zur Tumorantigenvakzinierung sind inzwischen initiiert. Eine Korrelation von klinischem Verlauf und Monitoring der Immuneffektoren nach Tumorvakzinierung kann mittels neuer immunologischer Techniken, die Immuneffektoren auf Einzelzellebene charakterisieren und in vivo verfolgen können, durchgeführt werden. Zukünftige immuntherapeutische klinische Studien lassen prognostische Parameter für bestimmte Patientenuntergruppen, optimierte Vakzinierungsprotokolle und neue immunologisch-molekulare Surrogatmarker für die Diagnostik von HCCs erwarten.

Abstract

Purpose: Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide. For most patients with advanced or multifocal HCC treatment options are limited resulting in a poor prognosis. Several local ablation methods have been developed as minimally invasive strategies for HCC treatment. It is unclear, until now, whether these therapies will significantly improve the poor prognosis of patients with unresectable HCC. Novel therapeutic strategies and a better understanding of HCC imunobiology are, therefore, urgently required.

Design: The scientific literature since 1970 in all languages cited in Medline was systematically reviewed. Results: Until now, a variety of specific and non-specific immunostimulatory strategies against HCC has been applied in preclinical experimental models with some promising results. The molecular characterization of HCC associated tumour antigens such as α-fetoprotein (AFP) and the increased understanding of the immunological pathways involved in liver and tumor immunology have paved the way for the design of promising gene-based cancer vaccines. The first phase I and II immunotherapeutic clinical trials based on dendritic cell immunotherapy and peptide vaccines are ongoing in HCC-patients. Clinical trials have, in general, demonstrated the safety of such strategies. Recently, exciting new immunological techniques and tools have been developed which allow to characterize antigen specific T cells at a single-cell level. In future, HCC specific tumor rejection antigens which can be used therapeutically have to be identified using microarray-based analysis. The different therapeutic modalities need to be compared directly resulting in optimised therapeutic approaches and the identification of sub-groups of HCC-patients responding favourably to treatment.

HCC - Immuntherapie - Gentherapie - Zytokine - dendritische Zellen - T-Zelle

HCC - immunotherapy - gene therapy - dendritic cells - T cell - cytokines

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