plenary session 1: opening, keynotes and reviews
Annals of Oncology
In chronic myeloid leukemia (CML) expression of the oncogenic p210 bcr-abl fusion protein is caused by the typical t(9;22)(q34;q11) translocation. Constitutive activation of this tyrosine kinase results in the characteristic leukemic phenotype of CML. Because of its explicit expression in CML cells p210 bcr-abl is a paradigmatic structure for targeted therapies. The 2-phenylaminopyrimidine derivative imatinib (Glivec) is a tyrosine kinase inhibitor (TKI) that interacts and inhibits ATP
... activation of p210 bcr-abl , induces apoptosis and results in clearance of the leukemic clone in CML patients. Several phase III trials showed highly significant superiority of imatinib over previous therapeutic modalities in chronic phase (CP) patients. However, a variety of mechanisms of resistance, including over-expression of p210 bcr-abl , point mutations of the imatinib binding region and/or clonal evolution, have been identified that may result in resistance to imatinib and eventually cause relapse of leukaemia. Additionally, in a minority of patients continuous treatment with imatinib is jeopardized by grade III/IV toxicities. Hence, alternative TKIs have been developed to overcome both imatinib resistance and/or intolerance. Dasatinib (Sprycel) is a bispecific TKI that interacts with both bcr-abl and src-kinases expressed in leukemic cells. Phase I data suggested a dosage of 70 mg bid that was used in a multi-centre phase II trial in a total of n=387 patients with a follow-up of 15.2 months. In these patients a CHR (complete hematologic response) was observed in 91% and a complete cytogenetic response (CCR) in 49%. Non-hematologic toxicities primarily were of low grade, however, a considerable number of patients showed fluid retention (pericardial and pleural effusion). Flanking mutation analysis demonstrated activity of dasatinib in almost all known point mutations. In contrast, nilotinib (Tasigna) is chemically related to imatinib and maintains target specificity towards p210 bcr-abl . Phase I data with this compound showed activity in all stages of CML at a dose of 400mg bid. A multi-centre phase II trial at this dose in a total of n=316 patients is ongoing. Interim data in n=279 patients after a follow-up of 6 months showed a CHR rate of 74%, a CCR rate of 34% and an acceptable toxicity profile. Comparable to dasatinib molecular biology data of this trial confirmed activity in almost all known point mutations. In conclusion, both nilotinib and dasatinib represent novel second generation TKI in CP CML patients resistant or intolerant to imatinib. In the past two decades, immunotherapy approaches have been shown to be effective for the treatment of selected patients with metastatic cancer. The administration of interleukin-2 or a monoclonal antibody against CTLA-4 can mediate objective regression of metastatic melanoma in about 15% of patients. The administration of in vitro expanded autologous anti-tumor T cells, plus IL-2, following a lymphodepleting chemotherapy results in the objective regressions in approximately 50% of patients with metastatic melanoma. T cells capable of mediating these regressions have been used to identify dozens of human cancer antigens. Recently, gene therapy approaches that utilize the transduction of genes encoding anti tumor T cell receptors have been shown to be effective and hold promise for the application of immunotherapy for the treatment of patients with common epithelial cancers.