National Center for Asbestos Related Diseases

Nedlands, Australia

National Center for Asbestos Related Diseases

Nedlands, Australia
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Nowak A.K.,Sir Charles Gairdner Hospital | Nowak A.K.,University of Western Australia | Nowak A.K.,National Center for Asbestos Related Diseases | Brown C.,University of Sydney | And 16 more authors.
Lung Cancer | Year: 2013

BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16mg/m2 was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%); 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4); median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent. © 2013 Elsevier Ireland Ltd.

Steven A.,University of Western Australia | Steven A.,National Center for Asbestos Related Diseases | Fisher S.A.,University of Western Australia | Fisher S.A.,National Center for Asbestos Related Diseases | And 2 more authors.
Respirology | Year: 2016

Treatment of lung cancer remains a challenge, and lung cancer is still the leading cause of cancer-related mortality. Immunotherapy has previously failed in lung cancer but has recently emerged as a very effective new therapy, and there is now growing worldwide enthusiasm in cancer immunotherapy. We summarize why immune checkpoint blockade therapies have generated efficacious and durable responses in clinical trials and why this has reignited interest in this field. Cancer vaccines have also been explored in the past with marginal success. Identification of optimal candidate neoantigens may improve cancer vaccine efficacy and may pave the way to personalized immunotherapy, alone or in combination with other immunotherapy such as immune checkpoint blockade. Understanding the steps in immune recognition and eradication of cancer cells is vital to understanding why previous immunotherapies failed and how current therapies can be used optimally. We hold an optimistic view for the future prospect in lung cancer immunotherapy. © 2016 Asian Pacific Society of Respirology

McDonnell A.M.,University of Western Australia | McDonnell A.M.,National Center for Asbestos Related Diseases | Lesterhuis W.J.,University of Western Australia | Lesterhuis W.J.,National Center for Asbestos Related Diseases | And 11 more authors.
OncoImmunology | Year: 2015

Tumor antigen cross-presentation by dendritic cells (DCs) to specific CD8+ T cells is central to antitumor immunity. Although highly efficient in draining lymph nodes, it is defective within the tumor site itself. Importantly, an immunogenic chemotherapy, gemcitabine, reverses this defect, allowing the potential re-stimulation of cytotoxic T lymphocytes within tumor sites. © 2015 Taylor & Francis Group, LLC.

Anyaegbu C.C.,National Center for Asbestos Related Diseases | Anyaegbu C.C.,University of Western Australia | Lake R.A.,National Center for Asbestos Related Diseases | Lake R.A.,University of Western Australia | And 5 more authors.
PLoS ONE | Year: 2014

Cross-presentation of tumor antigen is essential for efficient priming of naïve CD8+T lymphocytes and induction of effective anti-tumor immunity. We hypothesized that the subcellular location of a tumor antigen could affect the efficiency of cross-presentation, and hence the outcome of anti-tumor responses to that antigen. We compared cross-presentation of a nominal antigen expressed in the nuclear, secretory, or cytoplasmic compartments of B16 melanoma tumors. All tumors expressed similar levels of the antigen. The antigen was cross-presented from all compartments but when the concentration was low, nuclear antigen was less efficiently cross-presented than antigen from other cellular locations. The efficiency of cross-presentation of the nuclear antigen was improved following chemotherapy-induced tumor cell apoptosis and this correlated with an increase in the proportion of effector CTL. These data demonstrate that chemotherapy improves nuclear tumor antigen cross-presentation and could be important for anti-cancer immunotherapies that target nuclear antigens. © 2014 Anyaegbu et al.

Nowak A.K.,Sir Charles Gairdner Hospital | Nowak A.K.,University of Western Australia | Nowak A.K.,National Center for Asbestos Related Diseases | Millward M.J.,Sir Charles Gairdner Hospital | And 19 more authors.
Journal of Thoracic Oncology | Year: 2012

INTRODUCTION:: There is no accepted second-line therapy for patients with advanced malignant pleural mesothelioma (MPM), whose disease has progressed after first-line chemotherapy. The multitargeted tyrosine kinase inhibitor sunitinib malate targets several pathways overexpressed in mesothelioma. This phase II study assessed objective response to sunitinib and correlative biomarkers in patients with progressive pretreated MPM. METHODS:: Eligible patients had confirmed MPM, radiological progression after chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 1, and measurable disease. Patients received oral sunitinib 50 mg daily for 28 of every 42 days. The primary endpoint was objective radiological response. Patients without prior pleurodesis had fluorodeoxyglucose positron emission tomographic response assessed by total glycolytic volume criteria. Correlative biomarkers included serum mesothelin, vascular endothelial growth factor (VEGF)-A, VEGF-C, interleukin-8, sVEGFR-2, sVEGFR-3, and s-kit. RESULTS:: Fifty-three patients received sunitinib between July 2006 and December 2009; 51 were assessable for response. Patients received a median of two cycles (range, 1-12); 40% required dose reduction. Fatigue was the most prominent toxicity. Six patients (12%) had a confirmed radiological partial response, 34 (65%) had stable disease, and 11 (22%) had progressive disease as best response. Six of 20 patients had a decrease in fluorodeoxyglucose positron emission tomographic total glycolytic volume of 15% or more. Median overall survival was 6.1 months, and median time to progression was 3.5 months. Correlative biomarkers did not predict treatment response. CONCLUSIONS:: Sunitinib has activity in a subset of patients with pretreated MPM. Consideration should be given to different treatment schedules and examination of other biomarkers for further study of sunitinib in MPM. © 2012 by the International Association for the Study of Lung.

McCoy M.J.,University of Western Australia | McCoy M.J.,National Center for Asbestos Related Diseases | Lake R.A.,University of Western Australia | Lake R.A.,National Center for Asbestos Related Diseases | And 7 more authors.
British Journal of Cancer | Year: 2012

Background: There is increasing interest in combining chemotherapy with immunotherapy. However, the effects of chemotherapy on the human immune system are largely unknown. Methods: Longitudinal changes in peripheral T-cell subsets in 40 patients with malignant mesothelioma (MM) or advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy were assessed by flow cytometry and evaluated for associations with clinical outcome. Results: Proliferating T cells of all subsets were almost entirely depleted at day 8 following chemotherapy, but rapidly recovered above baseline levels. Regulatory T cells (Treg) were most profoundly depleted at this time point. A greater increase in CD8+ T-cell proliferation following one treatment cycle was associated with improved overall survival in univariate (hazard ratio (HR)0.40; P=0.05) and multivariate (HR0.17; P=0.01) analyses. A greater increase in the ratio of CD8+ T cell to Treg proliferation was also predictive of better prognosis.Conclusion:Chemotherapy potentially provides a favourable environment for the development of anti-tumour immunity through transient Treg depletion and regeneration of the T-cell pool. Change in CD8 + T-cell proliferation after one cycle of chemotherapy may represent a useful prognostic indicator in patients with MM and NSCLC. © 2012 Cancer Research UK All rights reserved.

Khong A.,University of Western Australia | Nelson D.J.,Curtin University Australia | Nowak A.K.,University of Western Australia | Nowak A.K.,National Center for Asbestos Related Diseases | And 5 more authors.
International Reviews of Immunology | Year: 2012

Agonistic anti-CD40 antibody is a potent stimulator of anti-tumor immune responses due to its action on both immune and tumor cells. It has the ability to "precondition" dendritic cells, allowing them to prime effective cytotoxic T-cell responses. Thus, anti-CD40 antibody provides an ideal therapy for combination with traditional cancer treatments (i.e., chemotherapy, surgery) in order to elicit immune-mediated anti-tumor effects. This review summarizes the mechanisms of action of agonistic anti-CD40, the use of mouse models to investigate its effects and combinations with other therapies in vivo, and current clinical trials combining humanized anti-CD40 antibody with chemotherapy and/or other immunotherapies. Copyright © 2012 Informa Healthcare USA, Inc.

McDonnell A.M.,University of Western Australia | Robinson B.W.S.,University of Western Australia | Robinson B.W.S.,National Center for Asbestos Related Diseases | Currie A.J.,University of Western Australia | Currie A.J.,Murdoch University
Clinical and Developmental Immunology | Year: 2010

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that are critical for the generation of effective cytotoxic T lymphocyte (CTL) responses; however, their function and phenotype are often defective or altered in tumor-bearing hosts, which may limit their capacity to mount an effective tumor-specific CTL response. In particular, the manner in which exogenous tumor antigens are acquired, processed, and cross-presented to CD8 T cells by DCs in tumor-bearing hosts is not well understood, but may have a profound effect on antitumor immunity. In this paper, we have examined the role of DCs in the cross-presentation of tumor antigen in terms of their subset, function, migration, and location with the intention of examining the early processes that contribute to the development of an ineffective anti-tumor immune response. Copyright © 2010 Alison M. McDonnell et al.

McCoy M.J.,University of Western Australia | McCoy M.J.,National Center for Asbestos Related Diseases | McCoy M.J.,Sir Charles Gairdner Hospital | Nowak A.K.,University of Western Australia | And 8 more authors.
Cancer Immunology, Immunotherapy | Year: 2013

There is a complex interplay between the immune system and a developing tumor that is manifest in the way that the balance of T cell subsets in the local tumor environment reflects clinical outcome. Tumor infiltration by CD8+ T cells and regulatory T cells (Treg) is associated with improved and reduced survival, respectively, in many cancer types. However, little is known of the prognostic value of immunological parameters measured in peripheral blood. In this study, peripheral CD8+ T cells and Treg from 43 patients with malignant mesothelioma or advanced non-small-cell lung cancer scheduled to commence palliative chemotherapy were assessed by flow cytometry and evaluated for association with patient survival. Patients had a higher proportion of peripheral Treg, proliferating CD8+ T cells and CD8+ T cells with an activated effector phenotype compared with age-matched healthy controls. Higher proportions of Treg and proliferating CD8+ T cells were both associated with poor survival in univariate analyses (hazard ratio [HR] 3.81, 95 % CI 1.69-8.57; p < 0.01 and HR 2.86, 95 % CI 1.26-6.50; p < 0.05, respectively). CD8+ T cell proliferation was independently predictive of reduced survival in multivariate analysis (HR 2.58, 95 % CI 1.01-6.61; p < 0.05). These findings suggest that peripheral CD8+ T cell proliferation can be a useful prognostic marker in patients with thoracic malignancies planned for palliative chemotherapy. © 2012 Springer-Verlag Berlin Heidelberg.

Cook A.M.,University of Western Australia | Cook A.M.,National Center for Asbestos Related Diseases | McDonnell A.M.,University of Western Australia | McDonnell A.M.,National Center for Asbestos Related Diseases | And 5 more authors.
OncoImmunology | Year: 2016

ABSTRACT: The glucocorticoid (GC) steroid dexamethasone (Dex) is used as a supportive care co-medication for cancer patients undergoing standard care pemetrexed/platinum doublet chemotherapy. As trials for new cancer immunotherapy treatments increase in prevalence, it is important to track the immunological changes induced by co-medications commonly used in the clinic, but not specifically included in trial design or in pre-clinical models. Here, we document a number of Dex -induced immunological effects, including a large-scale lymphodepletive effect particularly affecting CD4+T cells but also CD8+T cells. The proportion of regulatory T cells within the CD4+compartment did not change after Dex was administered, however a significant increase in proliferation and activation of regulatory T cells was observed. We also noted Dex -induced proportional changes in dendritic cell (DC) subtypes. We discuss these immunological effects in the context of chemoimmunotherapy strategies, and suggest a number of considerations to be taken into account when designing future studies where Dex and other GCs may be in use. © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC.

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