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Brown M.P.,Cancer Clinical Trials Unit
Immunotherapy | Year: 2011

For the first time, a pivotal Phase III clinical trial has demonstrated an overall survival benefit for an antimelanoma drug, ipilimumab, in previously treated advanced melanoma patients. Ipilimumab is a T-cell-potentiating monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4. All patients in this study were HLA-A2*0201 positive because the active control arm contained a HLA-A2*0201-restricted peptide derived from the melanocyte differentiation antigen, gp100. Hence, the following question arises: does the survival benefit conferred by ipilimumab treatment only benefit HLA-A2*0201-positive melanoma patients? However, the current paper reveals a retrospective analysis to show that advanced melanoma patients obtain a survival benefit from ipilimumab irrespective of HLA-A2*0201 status. This analysis also raises other interesting questions regarding the HLA dependence of mechanisms underlying the toxicity and antimelanoma activity of ipilimumab, which are discussed. © 2011 Future Medicine Ltd. Source


Al-Ejeh F.,Queensland Institute of Medical Research | Smart C.E.,University of Queensland | Morrison B.J.,Queensland Institute of Medical Research | Chenevix-Trench G.,Queensland Institute of Medical Research | And 6 more authors.
Carcinogenesis | Year: 2011

The clinical and pathologic heterogeneity of human breast cancer has long been recognized. Now, molecular profiling has enriched our understanding of breast cancer heterogeneity and yielded new prognostic and predictive information. Despite recent therapeutic advances, including the HER2-specific agent, trastuzumab, locoregional and systemic disease recurrence remain an ever-present threat to the health and well being of breast cancer survivors. By definition, disease recurrence originates from residual treatment-resistant cells, which regenerate at least the initial breast cancer phenotype. The discovery of the normal breast stem cell has reignited interest in the identity and properties of breast cancer stem-like cells and the relationship of these cells to the repopulating ability of treatment-resistant cells. The cancer stem cell model of breast cancer development contrasts with the clonal evolution model, whereas the mixed model draws on features of both. Although the origin and identity of breast cancer stem-like cells is contentious, treatment-resistant cells survive and propagate only because aberrant and potentially druggable signaling pathways are recruited. As a means to increase the rates of breast cancer cure, several approaches to specific targeting of the treatment-resistant cell population exist and include methods for addressing the problem of radioresistance in particular. © The Author 2011. Published by Oxford University Press. All rights reserved. Source


Harata-Lee Y.,University of Adelaide | Turvey M.E.,University of Adelaide | Brazzatti J.A.,University of Adelaide | Brazzatti J.A.,University of Manchester | And 6 more authors.
Immunology and Cell Biology | Year: 2014

Over the last decade, the significance of the homeostatic CC chemokine receptor-7 and its ligands CC chemokine ligand-19 (CCL19) and CCL21, in various types of cancer, particularly mammary carcinoma, has been highlighted. The chemokine receptor CCX-CKR is a high-affinity receptor for these chemokine ligands but rather than inducing classical downstream signalling events promoting migration, it instead sequesters and targets its ligands for degradation, and appears to function as a regulator of the bioavailability of these chemokines in vivo. Therefore, in this study, we tested the hypothesis that local regulation of chemokine levels by CCX-CKR expressed on tumours alters tumour growth and metastasis in vivo. Expression of CCX-CKR on 4T1.2 mouse mammary carcinoma cells inhibited orthotopic tumour growth. However, this effect could not be correlated with chemokine scavenging in vivo and was not mediated by host adaptive immunity. Conversely, expression of CCX-CKR on 4T1.2 cells resulted in enhanced spontaneous metastasis and haematogenous metastasis in vivo. In vitro characterisation of the tumourigenicity of CCX-CKR-expressing 4T1.2 cells suggested accelerated epithelial-mesenchymal transition (EMT) revealed by their more invasive and motile character, lower adherence to the extracellular matrix and to each other, and greater resistance to anoikis. Further analysis of CCX-CKR-expressing 4T1.2 cells also revealed that transforming growth factor (TGF)-β1 expression was increased both at mRNA and protein levels leading to enhanced autocrine phosphorylation of Smad 2/3 in these cells. Together, our data show a novel function for the chemokine receptor CCX-CKR as a regulator of TGF-β1 expression and the EMT in breast cancer cells. © 2014 Australasian Society for Immunology Inc. Source


Brown M.P.,Cancer Clinical Trials Unit | Brown M.P.,University of Adelaide | Staudacher A.H.,University of Adelaide | Staudacher A.H.,Center for Cancer Biology
Immunotherapy | Year: 2014

Evaluation of: Younes A, Connors JM, Park SI et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a Phase 1, open-label, dose-escalation study. Lancet Oncol. 14(13), 1348-1356 (2013). With exceptionally high response rates, the CD30-directed antibody-drug conjugate brentuximab vedotin (BV) was US FDA approved for treatment of patients with relapsed/refractory Hodgkin lymphoma (HL). Now in Phase I clinical trial, it has been shown that combining BV with multiagent chemotherapy (excluding bleomycin) as first-line treatment in HL patients with high-risk disease is feasible. Complete response rates were over 90% and toxicity was manageable. Given that the malignant cell population comprises a minority of HL lesions, and that BV releases a diffusible cytotoxin via a cathepsin B-cleavable linker, we argue that a significant proportion of the antitumor activity of BV can be attributed to bystander cytotoxicity in addition to direct killing of CD30-expressing malignant cells. © 2014 Future Medicine Ltd. Source


Bambury R.M.,Sloan Kettering Cancer Center | Morris P.G.,Sloan Kettering Cancer Center | Morris P.G.,Cancer Clinical Trials Unit
Expert Review of Anticancer Therapy | Year: 2014

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with ≤10% patients surviving 5 years from the time of diagnosis. After tumor progression on frontline therapy with concomitant chemoradiotherapy followed by consolidation temozolomide there are few effective treatment options. Bevacizumab and nitrosureas are the most commonly used systemic options in this instance but no overall survival benefit has been demonstrated. In this review we outline the major avenues of research for treatment of recurrent GBM including anti-angiogenic, signaling pathway blockade and immunotherapy approaches. Results of recent trials as well as pertinent ongoing studies are discussed. Enrollment of patients to clinical trials as well as incorporation of correlative translational science studies to identify predictive biomarkers of treatment response will be key to improving outcomes in this devastating disease. © 2014 Informa UK, Ltd. Source

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