Human tumour immune evasion via TGF-ß blocks NK cell activation but not survival allowing therapeutic restoration of anti-tumour activity.

Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-ß. Release from TGF-ß-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-ß dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-ß dependent inhibition upon autologous NK cells ex vivo. TGF-ß antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-ß treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-ß blockade and both anti-TGF-ß antibodies and a small molecule inhibitor of TGF-ß signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-ß blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity.

Clinical utility of image-guided peritoneal and omental biopsy.

Image-guided core biopsy of the omentum and peritoneum was described a decade ago and has since been validated in a number of large studies as a safe and effective means of providing a tissue diagnosis in patients with undiagnosed peritoneal disease. Some studies have addressed its ability for determining whether peritoneal infiltration and/or omental masses in patients with prior malignancy represent recurrent disease or a new disease process. Others have focused on the specific issue of women suspected to have advanced peritoneal carcinomatosis from ovarian or primary peritoneal cancer where the primary management of the patient is directed by the tissue diagnosis. The initial management of many of these women, especially those with advanced disease or substantial comorbidity, is with primary chemotherapy. With current clinical trials for ovarian cancer directed to specific morphological subtypes of the disease, image-guided core biopsy offers a rapid and well tolerated nonsurgical means of providing this information. In this Review, we discuss the technique and its clinical applications, and critically examine the currently available alternative options.

Proteomic profiling identifies afamin as a potential biomarker for ovarian cancer.

PURPOSE: To discover and validate serum glycoprotein biomarkers in ovarian cancer using proteomic-based approaches. EXPERIMENTAL DESIGN: Serum samples from a "discovery set" of 20 patients with ovarian cancer or benign ovarian cysts or healthy volunteers were compared by fluorescence two-dimensional differential in-gel electrophoresis and parallel lectin-based two-dimensional profiling. Validation of a candidate biomarker was carried out with Western blotting and immunoassay (n = 424). RESULTS: Twenty-six proteins that changed significantly were identified by mass spectrometric sequencing. One of these, confirmed by Western blotting, was afamin, a vitamin E binding protein, with two isoforms decreasing in patients with ovarian cancer. Validation using cross-sectional samples from 303 individuals (healthy controls and patients with benign, borderline, or malignant ovarian conditions and other cancers) assayed by ELISA showed significantly decreased total afamin concentrations in patients with ovarian cancer compared with healthy controls (P = 0.002) and patients with benign disease (P = 0.046). However, the receiver operating characteristic areas for total afamin for the comparison of ovarian cancer with healthy controls or benign controls were only 0.67 and 0.60, respectively, with comparable figures for CA-125 being 0.92 and 0.88 although corresponding figures for a subgroup of samples analyzed by isoelectric focusing for afamin isoform 2 were 0.85 and 0.79. Analysis of a further 121 samples collected prospectively from 9 patients pretreatment through to relapse indicated complementarity of afamin with CA-125, including two cases in whom CA-125 was noninformative. CONCLUSIONS: Afamin shows potential complementarity with CA-125 in longitudinal monitoring of patients with ovarian cancer, justifying prospective larger-scale investigation. Changes in specific isoforms may provide further information.

Systemic chemotherapy for patients with bladder cancer--current controversies and future directions.

Many localised, superficial bladder cancers can be effectively controlled. However, disease which has spread to nodes outside the pelvis or to distant organs is generally incurable and systemic therapies, rather than surgery, are appropriate. Combination chemotherapy based around established cytotoxic drugs such as cisplatin has proven benefit in palliating symptoms and prolonging survival in responsive patients with advanced disease. Combination chemotherapies which include newer cytotoxic drugs such as gemcitabine provide the potential for equivalent efficacy with less toxicity than established regimens. Between the extremes of superficial and advanced disease, muscle-invasive bladder cancers have traditionally been treated, with curative intent, by radical surgery or radiotherapy. However, newly published data suggest, for the first time, genuine survival benefits from peri-operative chemotherapy. This article reviews the evidence for cisplatin-based chemotherapy in advanced disease, assesses the potential benefits of newer cytotoxic drugs, discusses the latest evidence pertaining to peri-operative chemotherapy in muscle-invasive disease, and looks forward to potential new biological agents in the systemic therapy of bladder cancer.

Phase I and pharmacokinetic study of intravenous irinotecan plus oral ciclosporin in patients with fuorouracil-refractory metastatic colon cancer.

PURPOSE: To assess the safety and toxicity profile of escalating doses of intravenous irinotecan, in combination with a fixed dose of oral ciclosporin (Cs) and to determine the pharmacokinetic profile of irinotecan and its metabolites. PATIENTS AND METHODS: Patients with fluorouracil-refractory metastatic colorectal cancer received escalating doses of intravenous irinotecan from 40 to 125 mg/m(2) every 2 weeks in combination with a fixed dose of oral Cs (5 mg/kg bid for 3 days). Pharmacokinetic analysis of plasma irinotecan and its metabolites SN38 and SN38G was performed during paired cycles with and without Cs. RESULTS: Thirty-seven patients were treated. Dose-limiting toxicity of grade 4 neutropenia was seen at an irinotecan dose of 125 mg/m(2). There was no grade 4 diarrhea, and only one patient experienced grade 3 diarrhea. Toxicities caused by Cs were generally mild. Pharmacokinetic studies demonstrated that irinotecan clearance was reduced from 13.4 to 5.8 L/h/m(2) and area under the curve (AUC)(0-tn) was increased 2.2-fold by the coadministration of Cs. Similar significant increases in AUC(0-24h) were seen for both SN38 and SN38G (2.2-fold and 2.3-fold, respectively) in the presence of Cs. Antitumor activity was seen at every irinotecan dose level. CONCLUSION: The maximum tolerated irinotecan dose and recommended dose for phase II studies is 100 mg/m(2) every 2 weeks. Dose-limiting diarrhea was not seen during this study, supporting the hypothesis that pharmacokinetic modulation of irinotecan by Cs may improve its therapeutic index. Further studies using this combination are warranted.