Fiona Elsey Cancer Research Institute

Ballarat, Australia

Fiona Elsey Cancer Research Institute

Ballarat, Australia

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Chan A.C.,University of Melbourne | Neeson P.,University of Melbourne | Leeansyah E.,University of Melbourne | Quach H.,University of Melbourne | And 7 more authors.
Clinical and Experimental Immunology | Year: 2014

The causes of multiple myeloma (MM) remain obscure and there are few known risk factors; however, natural killer T (NKT) cell abnormalities have been reported in patients with MM, and therapeutic targeting of NKT cells is promoted as a potential treatment. We characterized NKT cell defects in treated and untreated patients with MM and determined the impact of lenalidomide therapy on the NKT cell pool. Lenalidomide is an immunomodulatory drug with co-stimulatory effects on NKT cells in vitro and is an approved treatment for MM, although its mode of action in that context is not well defined. We find that patients with relapsed/progressive MM had a marked deficiency in NKT cell numbers. In contrast, newly diagnosed patients had relatively normal NKT cell frequency and function prior to treatment, although a specific NKT cell deficiency emerged after high-dose melphalan and autologous stem cell transplantation (ASCT) regimen. This also impacted NK cells and conventional T cells, but the recovery of NKT cells was considerably delayed, resulting in a prolonged, treatment-induced NKT cell deficit. Longitudinal analysis of individual patients revealed that lenalidomide therapy had no in-vivo impact on NKT cell numbers or cytokine production, either as induction therapy, or as maintenance therapy following ASCT, indicating that its clinical benefits in this setting are independent of NKT cell modulation. © 2013 British Society for Immunology.


Chan A.C.,University of Melbourne | Leeansyah E.,University of Melbourne | Leeansyah E.,Karolinska University Hospital | Cochrane A.,Monash University | And 7 more authors.
Clinical and Experimental Immunology | Year: 2013

Summary: Our understanding of human type 1 natural killer T (NKT) cells has been heavily dependent on studies of cells from peripheral blood. These have identified two functionally distinct subsets defined by expression of CD4, although it is widely believed that this underestimates the true number of subsets. Two recent studies supporting this view have provided more detail about diversity of the human NKT cells, but relied on analysis of NKT cells from human blood that had been expanded in vitro prior to analysis. In this study we extend those findings by assessing the heterogeneity of CD4+ and CD4- human NKT cell subsets from peripheral blood, cord blood, thymus and spleen without prior expansion ex vivo, and identifying for the first time cytokines expressed by human NKT cells from spleen and thymus. Our comparative analysis reveals highly heterogeneous expression of surface antigens by CD4+ and CD4- NKT cell subsets and identifies several antigens whose differential expression correlates with the cytokine response. Collectively, our findings reveal that the common classification of NKT cells into CD4+ and CD4- subsets fails to reflect the diversity of this lineage, and that more studies are needed to establish the functional significance of the antigen expression patterns and tissue residency of human NKT cells.© 2012 British Society for Immunology.


Escudier B.,Institute Gustave Roussy | Michaelson M.D.,Massachusetts General Hospital | Motzer R.J.,Sloan Kettering Cancer Center | Hutson T.E.,Sammons Cancer Center | And 12 more authors.
British Journal of Cancer | Year: 2014

Background:In the AXIS trial, axitinib prolonged progression-free survival (PFS) vs sorafenib in patients with advanced renal cell carcinoma (RCC) previously treated with sunitinib or cytokines.Methods:In post hoc analyses, patients were grouped by objective response to prior therapy (yes vs no), prior therapy duration (< vs ≥median), and tumour burden (baseline sum of the longest diameter < vs ≥median). PFS and overall survival (OS), and safety by type and duration of prior therapy were evaluated.Results:Response to prior therapy did not influence outcome with second-line axitinib or sorafenib. PFS was significantly longer in axitinib-treated patients who received longer prior cytokine treatment and sorafenib-treated patients with smaller tumour burden following sunitinib. Overall survival with the second-line therapy was longer in patients who received longer duration of prior therapy, although not significant in the sunitinib-to-axitinib sequence subgroup; OS was also longer in patients with smaller tumour burden, but not significant in the cytokine-to-axitinib sequence subgroup. Safety profiles differed modestly by type and duration of prior therapy.Conclusions:AXIS data suggest that longer duration of the first-line therapy generally yields better outcome with the second-line therapy and that lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line vascular endothelial growth factor-targeted agent in patients with advanced RCC. © 2014 Cancer Research UK.


Karakiewicz P.I.,University of Montréal | Nott L.,Royal Hobart Hospital | Joshi A.,James Cook University | Kannourakis G.,Fiona Elsey Cancer Research Institute | And 2 more authors.
OncoTargets and Therapy | Year: 2016

Background: Axitinib, a selective and potent tyrosine kinase inhibitor of vascular endothelial growth factor receptors, was available to patients from Canada and Australia, prior to regulatory approval of axitinib in these countries, for treatment of clear-cell metastatic renal cell carcinoma (mRCC) after failure of one prior systemic regimen. Methods: This single-arm, open-label study of axitinib evaluated the efficacy, safety, and quality of life (QoL) in patients with mRCC whose disease progressed after one prior systemic first-line regimen. Primary objective was objective response rate evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) and Choi criteria. Progression-free survival, overall survival, safety, and QoL were secondary end points. Due to the small study size, analyses comprised of descriptive statistics. Results: Fifteen patients were recruited, five from Canada and ten from Australia, over a limited recruitment period. Thirteen patients received sunitinib as prior therapy. All patients had clear-cell carcinoma, eleven had prior nephrectomy. Liver, lung, and lymph nodes were the most frequent sites of metastases; one patient had brain metastasis. Median time on axitinib was 118.0 days (range: 3.5-645.0 days); estimated survival probability at 12 months was 57.8%. Two (13.3%) patients had objective responses per RECIST versus nine (60.0%) per Choi criteria. Six patients had progressive disease based on RECIST versus three per Choi criteria. Nine (60.0%) events of progression or death occurred by the end of study, and three patients continued to receive the study drug. Fatigue (33%) and diarrhea (20%) were the most common grade $3 all-causality, treatment-emergent adverse events. The mean change in European Quality of Life - 5 Dimensions score from baseline to end of treatment was −0.0837. Conclusion: The small number of patients and lack of a comparator arm limit the ability to draw definitive conclusions; however, safety and efficacy profiles of axitinib were consistent with reports from previous studies in patients with mRCC, and patients generally maintained QoL. The sizeable difference observed in objective response rate by RECIST versus Choi criteria merits further research. © 2016 Karakiewicz et al.


PubMed | Fiona Elsey Cancer Research Institute, Karolinska University Hospital, University of Ballarat and University for Information Science and Technology
Type: Journal Article | Journal: PloS one | Year: 2014

Langerhans cell histiocytosis (LCH) is a complex and poorly understood disorder that has characteristics of both inflammatory and neoplastic disease. By using eight-colour flow cytometry, we have identified a previously unreported population of CD1a(+)/CD3(+) T-cells in LCH lesions. The expression of CD1a is regarded as a hallmark of this disease; however, it has always been presumed that it was only expressed by pathogenic Langerhans cells (LCs). We have now detected CD1a expression by a range of T-cell subsets within all of the LCH lesions that were examined, establishing that CD1a expression in these lesions is no longer restricted to pathogenic LCs. The presence of CD1a(+) T-cells in all of the LCH lesions that we have studied to date warrants further investigation into their biological function to determine whether these cells are important in the pathogenesis of LCH.


Chilton W.L.,University of Vic | Marques F.Z.,University of Vic | West J.,Fiona Elsey Cancer Research Institute | Kannourakis G.,Fiona Elsey Cancer Research Institute | And 3 more authors.
PLoS ONE | Year: 2014

Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health. © 2014 Chilton et al.


Berzins S.P.,University of Vic | Berzins S.P.,Fiona Elsey Cancer Research Institute | Berzins S.P.,University of Melbourne | Ritchie D.S.,Royal Melbourne Hospital | Ritchie D.S.,University of Melbourne
Nature Reviews Immunology | Year: 2014

Natural killer T (NKT) cells are credited with regulatory roles in immunity against cancers, autoimmune diseases, allergies, and bacterial and viral infections. Studies in mice and observational research in patient groups have suggested that NKT cell-based therapies could be used to prevent or treat these diseases, yet the translation into clinical settings has been disappointing. We support the view that NKT cells have regulatory characteristics that could be exploited in clinical settings, but there are doubts about the natural roles of NKT cells in vivo and whether NKT cell defects are fundamental drivers of disease in humans. In this Opinion article, we discuss the uncertainties and opportunities regarding NKT cells in humans, and the potential for NKT cells to be manipulated to prevent or treat disease. © 2014 Macmillan Publishers Limited.


Wallace M.E.,University of Vic | Wallace M.E.,Fiona Elsey Cancer Research Institute | Alcantara M.B.,University of Vic | Alcantara M.B.,Fiona Elsey Cancer Research Institute | And 7 more authors.
International Immunopharmacology | Year: 2015

The last few years has seen the burgeoning of a new category of therapeutics for cancer targeting immune regulatory pathways. Antibodies that block the PD-1/PD-L1 interaction are perhaps the most prominent of these new anti-cancer therapies, but several other inhibitory receptor ligand interactions have also shown promise as targets in clinical trials, including CTLA-4/CD80 and Lag-3/MHC class II. Related to this is a rapidly improving knowledge of 'regulatory' lymphocyte lineages, including NKT cells, MAIT cells, B regulatory cells and others. These cells have potent cytokine responses that can influence the functioning of other immune cells and many researchers believe that they could be effective targets for therapies designed to enhance immune responses to cancer. This review will outline our current understanding of FOXP3 + 'Tregs', NKT cells, MAIT cells and B regulatory cells immune regulatory cell populations in cancer, with a particular focus on chronic lymphocytic leukaemia (CLL). We will discuss evidence linking CLL with immune regulatory dysfunction and the potential for new therapies targeting regulatory cells. © 2015 Elsevier B.V.


PubMed | Health Science University and Fiona Elsey Cancer Research Institute
Type: Clinical Trial | Journal: PloS one | Year: 2014

Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age=24.11.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P=0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health.


PubMed | Fiona Elsey Cancer Research Institute and University of Melbourne
Type: Evaluation Studies | Journal: Archives of virology | Year: 2015

During attempts to clone retroviral determinants associated with a mouse model of Langerhans cell histiocytosis (LCH), suppression subtractive hybridization (SSH) was used to identify unique viruses in the liver of severe combined immunodeficiency (SCID) mice transplanted with LCH tissues. A partial genomic sequence of a murine coronavirus was identified, and the whole genome (31428 bp) of the coronavirus was subsequently sequenced using PCR cloning techniques. Nucleotide sequence comparisons revealed that the genome sequence of the new virus was 91-93% identical to those of known murine hepatitis viruses (MHVs). The predicted open reading frame from the nucleotide sequence encoded all known proteins of MHVs. Analysis at the protein level showed that the virus was closely related to the highly virulent MHV-JHM strain. The virus strain was named MHV-MI. No type D retroviruses were found. Degenerate PCR targeting of type D retrovirus and 5-RACE targeting of other types of retroviruses confirmed the absence of any retroviral association with the LCH xenografted SCID mice.

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