[Esophageal carcinoma: non-surgical therapy]. / Osophaguskarzinom--Nicht-chirurgische Therapie.

Esophageal carcinoma is one of the most common cancers in the world. There is a rising incidence of adenocarcinoma of the esophagus in Western countries. The present standard of care of patients with early tumors (Tis-T1 N0-N1 M0) is surgery and there is no role for chemo- or radiotherapy. Surgical treatment of stage II patients with locally resectable tumors is associated with poor survival figures due to an increase of regional and distant lymph node metastases. Adjuvant chemotherapy should be used only in the setting of clinical trials. The role of neoadjuvant chemo-radiotherapy in patients with resectable tumors is controversial. There is also evidence that some patients with a complete response after chemo-radiotherapy do not have a further benefit from surgical treatment. Therefore, the appropriate application of these varied therapeutic interventions should be performed at specialized centers. The role of chemotherapy and radiation is now established in locally advanced inoperable disease. How best to deliver these modes of therapy has yet to be defined. Prospective randomised trials are the only way to define the best therapeutic strategies for the different subgroups of patients with esophageal carcinoma. Progress with newer chemotherapy agents, optimal radiotherapy protocols and innovations are likely to improve responses to combination treatments, but may more importantly limit associated toxicity. Future trials should also assess quality of life indices as end points, that are of particular importance in populations with a median survival of approx, one year. Patients with stage IVb esophageal carcinoma have a life expectancy of less than six months and palliative teatment strategies should primarily aim at the improvement of tumor related symptoms and the maintenance of nutrition.

Immunobiology and gene-based immunotherapy of hepatocellular carcinoma.

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 alpha-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.

Immunotherapy directed against alpha-fetoprotein results in autoimmune liver disease during liver regeneration in mice.

BACKGROUND & AIMS: Priming immune responses against alpha-fetoprotein (AFP) highly expressed in the majority of hepatocellular carcinomas results in significant antitumoral T-cell responses. Liver regeneration in humans and mice, however, is also associated with increased AFP expression. Therefore, we evaluated the risk of AFP-directed immunotherapeutic approaches to induce autoimmunity against the regenerating liver. METHODS: Mice were immunized with DNA encoding mouse AFP. For induction of liver regeneration, partial hepatectomy was performed and mice were monitored by serial histopathologic examinations and measurements of serum ALT activities (U/L), and by determination of the kinetics of AFP-specific T-cell responses. RESULTS: Livers of AFP immune mice without partial hepatectomy were characterized by minor lymphocytic infiltrations without transaminase elevations. By contrast, a significant hepatocyte damage was observed in regenerating liver that correlated well with the number of AFP-specific CD8(+) T cells, the activity of liver regeneration, and the level of AFP synthesis. Autoimmune liver damage was mediated by CD4(+) T cell-dependent CD8(+) cytotoxic T lymphocytes. CONCLUSIONS: These results show that priming of T-cell responses against shared tumor-specific self antigens may be accompanied by induction of autoimmunity dependent on the level of expression of the self antigen and have important implications for the development of antitumoral vaccines targeted against antigens that are not strictly tumor-specific.

Mouse alpha-fetoprotein-specific DNA-based immunotherapy of hepatocellular carcinoma leads to tumor regression in mice.

BACKGROUND & AIMS: alpha-Fetoprotein (AFP) is a tumor-associated protein that is frequently expressed at high levels in hepatocellular carcinoma (HCC). The aim of the study was to characterize self-reactive cytotoxic T lymphocytes (CTLs) directed against murine AFP (mAFP) after DNA-based immunization in mice. METHODS: To study CTL responses, mAFP-expressing recombinant vaccinia viruses were generated. An HCC tumor model was established in C57L/J mice by injection of syngeneic endogenously mAFP-expressing Hepa1-6 cells. RESULTS: Gene gun and intramuscular coimmunizations of DNA expression vectors encoding mAFP with plasmids encoding murine interleukin (IL)-12, granulocyte-macrophage colony-stimulating factor, or IL-18 induced weak CTL activity against mAFP in different mouse strains. Some mice developed anti-mAFP antibody responses, suggesting breaking of immunologic ignorance. No hepatocyte damage was detectable despite low-level endogenous hepatic mAFP expression. Therapeutic immunizations of mice bearing mAFP-expressing murine HCCs induced partial regression of tumors. A significant survival benefit was observed in mice immunized with mAFP expression vector DNA but not in untreated mice or in mice immunized with mock/cytokine plasmid DNA. CONCLUSIONS: The data show that AFP may be used as a potential self tumor antigen to induce CTL and CD4(+) T cell-mediated regression of AFP-expressing HCC by DNA-based immunization.