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Translational Oncology Laboratory

Translational Oncology Laboratory

Overview

In the Translational Oncology Laboratory, we are developing innovative new therapies for cancers including glioblastoma, melanoma and lung cancer, as well as novel approaches to better guide the use of existing therapies. We have a clear focus on the translation of our research to the clinic, enabling our discoveries to contribute to better patient outcomes as soon as possible.

Immunofluorescence staining of blood vessels in a glioblastoma tumour

Much of our research is collaborative, working in close association with the Cancer Clinical Trials Unit at the Royal Adelaide Hospital, and partnering with other clinical sites, research laboratories and industry partners around Australia and internationally.

There are two major research streams within the group: one focussed on T cell-based cancer immunotherapies, and the other on antibody-targeted diagnostics and therapeutics.

T Cell Immunotherapies: Researchers in this team focus on novel therapies that enhance a cancer patient’s immune system, to enable the patient’s own T cells to attack their cancer. Such approaches include chimeric antigen receptor (CAR)-T cell therapies and Immune Checkpoint Inhibitor (ICI) therapies.

Antibody Targeting: This team uses functionalised monoclonal antibodies, including antibody-drug conjugates (ADCs) and antibodies labelled with radioactive isotopes, to target tumour cells for therapeutic and diagnostic purposes.

Current Research Projects

Pre-clinical development of CAR-T cell therapies

Chimeric antigen receptor (CAR)-T cell therapy has revolutionised the treatment of certain blood cancers, and has spurred intense interest in extending these successes to the treatment of solid tumours.

Glioma neural stem cells growing in culture

We have a pre-clinical program to develop CAR-T cell therapy for solid cancers, with a particular focus on aggressive brain cancers (glioblastoma and diffuse midline glioma). We use patient-derived tumour and blood cells, as well as advanced mouse models and a novel tumour organoid system, to develop, optimise and test CAR-T cells for their ability to control tumour growth. Research programs in this area focus on identifying novel target antigens; improving the homing of CAR-T cells to tumour tissues; and optimising CAR-T cell survival and function.

CAR-T cell clinical trials

Our clinical program manufactures CAR-T cells targeting the GD2 tumour antigen here in Adelaide, using a protocol optimised in our pre-clinical research program. The GD2 molecule is expressed by many solid tumour types but has limited expression on healthy cells and tissues, making it an excellent CAR-T cell target. We are currently conducting a Phase 1 clinical trial at the Royal Adelaide Hospital (the CARPETS trial; ACTRN12613000198729), in which these GD2-targeting CAR-T cells are administered to patients with metastatic melanoma and other refractory solid tumours.

Flow cytometry analysis of T cells in the blood of a melanoma patient, identifying proliferating cells using Ki67

We also have plans to soon open two additional trials of GD2-targeting CAR-T cells: one in children with diffuse midline glioma (DMG) in collaboration with the Sydney Children’s Hospitals Network, and the other for adult glioblastoma patients at the Royal Adelaide Hospital.

Antibody Drug Conjugate (ADC) Technology

First-line therapy for lung cancer typically involves cytotoxic chemotherapy, which is DNA-damaging and causes cancer cell death. We have preclinical proof of concept for a novel method of detecting cancer cell death using the APOMAB® monoclonal antibody that is specific for the essential La ribonucleoprotein overexpressed in malignancy.

We are currently investigating the following applications of APOMAB®:

  • Antibody-drug conjugates (ADC) for bystander treatment of lung cancer: We are investigating ADC versions of APOMAB based on the premise that APOMAB-ADC-bound dead tumour cells are processed by both viable tumour cells and supporting leucocytes to produce bystander killing.
  • Preclinical development of an imaging agent for detection of cancer cell death:  We are adapting the APOMAB® monoclonal antibody for use in immuno-positron emission tomography (PET). Non-invasive methods for detecting cancer cell death can be useful for the early evaluation of therapeutic responses
  • Using ADCs to stimulate anti-tumour immune responses in models of cancer: We are using ADCs alone and in combination with immunotherapy agents to both directly kill tumour cells and to modulate the body’s immune system to more effectively target and eliminate any remaining resistant cancer cells.

Understanding and predicting patient responses to Immune Checkpoint Inhibitor (ICI) therapy

ICI therapy is a new therapeutic approach that is now approved in Australia for the treatment of several cancer types, including melanoma, lung and kidney cancers.

Haematoxylin & eosin (H&E) staining of a glioblastoma tumour displaying microvascular proliferation

These medicines can re-activate dormant anti-tumour immune responses, leading to dramatic tumour shrinkage, and possibly cure, in a fraction of patients. However, most patients receive little to no benefit, yet are still exposed to the risk of severe side effects. Using blood and tumour samples from melanoma patients, we are investigating the immune responses that underpin successful clinical outcomes following ICI therapy. This research may identify novel strategies to improve response rates, and is being used to develop a simple blood test to help guide the optimal treatment for each patient.

Recent publications

2021

  1. Truong NTH, Gargett T, Brown MP, Ebert LM (2021). Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies. Cancers 13 (9):2225. doi.org/10.3390/cancers13092225

  2. Yeo ECF, Brown MP, Gargett T, Ebert LM (2021) The Role of Cytokines and Chemokines in Shaping the Immune Microenvironment of Glioblastoma: Implications for Immunotherapy. Cells. 10(3):607. doi: 10.3390/cells10030607.

  3. Oksdath Mansilla M, Salazar-Hernandez C, Perrin SL, Scheer KG, Cildir G, Toubia J, Sedivakova K, Tea MN, Lenin S, Ponthier E, Yeo ECF, Tergaonkar V, Poonnoose S, Ormsby RJ, Pitson SM, Brown MP, Ebert LM, Gomez GA (2021). 3D-printed microplate inserts for long term high-resolution imaging of live brain organoids. BMC Biomed Eng. 3(1):6. doi: 10.1186/s42490-021-00049-5.

  4. Staudacher, A.H.*, Li, Y.*, Liapis, V. and Brown, M.P. (2021) The RNA-binding protein La/SSB associates with radiation-induced DNA double-strand breaks in lung cancer cell lines.  Cancer Reports, accepted for publication (*both authors contributed equally)

  5. Reid, P., Staudacher, A.H., Marcu, L.G., Olver, I., Moghaddasi, L., Brown, M.P., and Bezak, E. (2021). Characteristic differences in radiation-induced DNA damage response in HPV negative and HPV positive head and neck cancers with accumulation of fractional radiation dose. Head and Neck 46:10: 3086-3096

  6. Liapis, V., Tieu, W., Wittwer, N.L., Gargett, T., Evdokiou, A., Takhar, P., Rudd, S.E., Donnelly, P.S., Brown M.P. and Staudacher, A.H. (2021). Positron Emission Tomographic imaging of tumor cell death using Zirconium-89-labeled chimeric DAB4 following cisplatin chemotherapy in lung and ovarian cancer xenograft models.  Molecular Imaging and Biology, https://doi.org/10.1007/s11307-021-01640-x

  7. MacGregor, M., Shirazi, H.S., Chan, K.M., Ostrikov, K., McNicholas, K., Jay, A., Chong, M., Staudacher, A.H., Michl, T.D., Zhalgasbaikyzy, A., Brown, M.P., Kashani, M.N., Di Fiore, A., Grochowski, A., Robb, S., Belcher, S., Li, J., Gleadle, J.M. and Krasimir, V. (2021). Cancer cell detection device for the diagnosis of bladder cancer from urine.  Biosensors and Bioelectronics 171:112699 

2020

  1. Ebert LM, Yu W, Gargett T, Toubia J, Kollis PM, Tea MN, Ebert BW, Bardy C, van den Hurk M, Bonder CS, Manavis J, Ensbey KS, Oksdath Mansilla M, Scheer KG, Perrin SL, Ormsby RJ, Poonnoose S, Koszyca B, Pitson SM, Day BW, Gomez GA, Brown MP (2020). Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy. Clin Transl Immunology. 9(10):e1191.

  2. Zadeh Shirazi A, Fornaciari E, Bagherian NS, Ebert LM, Koszyca B, Gomez GA (2020). DeepSurvNet: Deep survival convolutional network for brain cancer survival rate classification based on histopathological images. Med Biol Eng Comput; 58:1031-1045

  3. Liapis, V., Tieu, W., Rudd, S.E., Donnelly, P.S., Wittwer, N.L., Brown M.P. and Staudacher, A.H. (2020). Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®.  EJNMMI Radiopharmacy and Chemistry 5(27)

  4. Staudacher, A.H.*, Liapis, V.*, Tieu, W., Wittwer, N.L. and Brown M.P. (2020). Tumour-associated macrophages process drug and radio-conjugates of the dead tumour cell targeting APOMAB antibody. Journal of Controlled Release 327(10): 779-787, (*both authors contributed equally)  

  5. Reid, P., Staudacher, A.H., Marcu, L.G., Olver, I., Moghaddasi, L., Brown, M.P., Li., Y. and Bezak, E. (2020). Intrinsic Radiosensitivity is not the determining factor in treatment response differences between HPV negative and HPV positive head and neck cancers.  Cells 9(8):1788 

  6. Reid, P., Staudacher, A.H., Marcu, L.G., Olver, I., Moghaddasi, L., Brown, M.P. and Bezak, E. (2020). Influence of the human papillomavirus on the radio-responsiveness of cancer stem cells in head and neck cancer.  Scientific Reports 10:2716

2019

  1. Gomez GA, Oksdath M, Brown MP, Ebert LM (2019). New approaches to model glioblastoma in vitro using brain organoids: implications for precision oncology. Transl Cancer Res; doi 10.21037/tcr.2019.09.08

  2. Brown MP, Ebert LM, Gargett T (2019). Clinical chimeric antigen receptor-T cell therapy: a new and promising treatment modality for glioblastoma. Clin Transl Immunology; 8:e1050.

  3. Gargett T, Truong N, Ebert LM, Yu W, Brown MP (2019). Optimization of manufacturing conditions for chimeric antigen receptor T cells to favor cells with a central memory phenotype. Cytotherapy; 21:593-602.

  4. Mencel J, Gargett T, Karanth N, Pokorny A, Brown MP, Charakidis M (2019). Thymic hyperplasia following double immune checkpoint inhibitor therapy in two patients with stage IV melanoma. Asia-Pacific Journal of Clinical-Oncology. First published: 01 August 2019 https://doi.org/10.1111/ajco.13233

  5. Perrin SL, Samuel MS, Koszyca B, Brown MP, Ebert LM*, Oksdath M*, Gomez GA* (2019). Glioblastoma heterogeneity and the tumour microenvironment: implications for preclinical research and development of new treatments. Biochem Soc Trans; 47(2):625-638. * Equal corresponding authors

  6. Ping Zhang, Jyothy Raju, M. Ashik Ullah, Raymond Au, Antiopi Varelias, Kate H. Gartlan, Stuart D. Olver, Luke D. Samson, Elise Sturgeon, Nienke Zomerdijk, Judy Avery, Tessa Gargett, Michael P. Brown, Lachlan J. Coin, Devika Ganesamoorthy, Cheryl Hutchins, Gary R. Pratt, Glen A. Kennedy, A. James Morton, Cameron I. Curley, Geoffrey R. Hill, and Siok-Keen Tey (2019). Phase I trial of inducible caspase 9 T cells in adult stem cell transplant demonstrates massive clonotypic proliferative potential and long-term persistence of transgenic T cells. Clinical Cancer Research; 25(6):1749-1755. doi: 10.1158/1078-0432.CCR-18-3069.

  7. Reid, P., Marcu, L.G., Olver, I., Moghaddasi, L., Staudacher, A.H., and Bezak, E. (2019) Diversity of cancer stem cells in head and neck carcinomas: the role of HPV in cancer stem cell heterogeneity, plasticity and treatment response.  Radiotherapy and Oncology 135:1-12.

  8. Staudacher, A.H., Li, Y., Liapis, V., Hou, J., Chin, D., Dolezal, O., Adams, T.E., van Berkel, P.H.  and Brown M.P. (2019).  APOMAB® antibody drug conjugates targeting dead tumor cells are effective in vivo.  Molecular Cancer Therapeutics 18(2): 335-345.

 2018

  1. T Gargett, M.N. Abbas, P. Rolan, J.D. Price, K.M. Gosling, A. Ferrante, I.I.C. Atmosukarto, J. Altin, C.R. Parish, M.P. Brown. (2018). Phase I Trial of Lipovaxin-MM, a Novel Dendritic Cell-Targeted Liposomal Vaccine for Malignant Melanoma. Cancer Immunology, Immunotherapy Jul 16. doi: 10.1007/s00262-018-2207-z.

  2. Ebert LM, Yu W, Gargett T, Brown MP (2018). Logic-gated approaches to extend the utility of chimeric antigen receptor T-cell technology. Biochem Soc Trans. 46:391

  3. Staudacher, A.H., Liapis, V. and Brown M.P. (2018). Therapeutic targeting of tumor hypoxia and necrosis with antibody α-radioconjugates.  Antibody Therapeutics 1:2 75-83.

  4. Reid, P., Puthenparampil, W, Li, Y., Marcu, L.G., Staudacher, A.H., Brown, M.P. and Bezak, E. (2018). Experimental investigation of radiobiology in head and neck cancer cell lines as a function of HPV status, by MTT assay.  Scientific Reports 8:7744 

2017

  1. Tan LY, Martini C, Fridlender ZG, Bonder CS , Brown MP, Ebert LM. (2017). Control of immune cell entry through the tumour vasculature: a missing link in optimising melanoma immunotherapy? Clin Transl Immunol, 6(3): e134.

  2. Hughes A, Clarson J, Gargett T, Yu W, Brown MP, Lopez AF, Hughes TP, Yong AS (2017). Comment on "KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study". Leuk Res. 55:55-57. doi: 10.1016/j.leukres.2017.01.009.

  3. Staudacher, A.H. and Brown M.P. (2017). Antibody drug conjugates and bystander killing – is antigen-dependent internalization required?  British Journal of Cancer 117: 1736-1742.

  4. Reid, P., Puthenparampil, W, Li, Y., Marcu, L.G., Staudacher, A.H., Brown, M.P. and Bezak, E. (2017). In vitro investigation of head and neck cancer stem cell proportions and their changes following X-ray irradiation as a function of HPV status. PLOS One. 12(10):e0186186. doi: 10.1371/journal.pone.0186186.

2016

  1. Tessa Gargett, Wenbo Yu, Malcolm Brenner, Gianpietro Dotti, Eric S. Yvon Susan N. Christo, John D. Hayball, Michael P. Brown. (2016). GD2-specific CAR T cells undergo potent activation and deletion following antigen stimulation but can be protected from induced cell death by PD-1 blockade. Mol Ther. 24(6):1135-1149. doi: 10.1038/mt.2016.63.

  2. Gargett T, Christo SN, Hercus TR, Abbas N, Singhal N, Lopez AF, Brown MP. (2016). Investigation of the in vitro effects of GM-CSF signalling blockade on differentiation and function of tumour-promoting Myeloid Derived Suppressor Cells (MDSC). Clin Transl Immunology, 5(12):e119. doi: 10.1038/cti.2016.80.

  3. Tan LY, Mintoff C, Johan MZ, Ebert BW, Fedele C, Zhang YF, Szeto P, Sheppard KE, McArthur GA, Foster-Smith E, Ruszkiewicz A, Brown MP, Bonder CS, Shackleton M, Ebert LM. (2016). Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome. Oncotarget. 7(29): 46492-46508.

  4. Al Darwish, R., Staudacher, A.H., Li, Y., Brown M.P. and Bezak, E. (2016). Development of a transmission alpha particle dosimetry technique using A549 cells and a Ra-223 source for targeted alpha therapy.  Medical Physics 43: 6145. 

2015

  1. Tessa Gargett, Michael P. Brown (2015). Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2. Cytotherapy, 17(4):487-95. doi: 10.1016/j.jcyt.2014.12.002.

  2. Tessa Gargett, Cara K. Fraser, Gianpietro Dotti, Eric S. Yvon, Michael P. Brown (2015). BRAF and MEK inhibition variably affect GD2-specific Chimeric Antigen Receptor (CAR) T cell function in vitro. J Immunother. 38(1):12-23.

  3. Al Darwish, R., Staudacher, A.H., Brown M.P. and Bezak, E. (2015). Autoradiography Imaging in Targeted Alpha Therapy with Timepix Detector.  Computational and Mathematical Methods in Medicine 2015:612580. doi: 10.1155/2015/612580

  4. Pishas, K.I., Adwal, A., Neuhaus, S.J., Clayer, M.T., Farshid, G., Staudacher, A.H. and Callen, D.F. (2015). XI-006 induces potent p53-independent apoptosis in Ewing sarcoma.  Scientific Reports 5: 11465.