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Translational Oncology Laboratory

Translational Oncology Laboratory

Research Program 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. 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. 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 analysing the results from 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. We are awaiting the opening of 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 and clinical development of an imaging agent for detection of cancer cell death:  We have adapted 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. Accordingly, we have opened a phase 1 clinical PET imaging trial at Royal Adelaide Hospital of 89Zr-APOMAB in cancer patients after various cancer treatments (Trial ID: ACTRN12620000622909).
  • 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 target and eliminate any remaining resistant cancer cells more effectively.

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. 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.

Select Recent Publications:

2022

  1. Gargett T, Ebert LM, Truong NTH, Kollis PM, Sedivakova K, Yu W, Yeo ECF, Wittwer NL, Gliddon BL, Tea MN, Ormsby R, Poonnoose S, Nowicki J, Vittorio O, Ziegler DS, Pitson SM, Brown MP (2022). GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma. J ImmunoTher Cancer 2022;10:e005187
  2. Kollis PM, Ebert LM, Toubia J, Bastow CR, Ormsby RJ, Poonnoose SI, Lenin S, Tea MN, Pitson SM, Gomez GA, Brown MP, Gargett T (2022). Characterising distinct migratory profiles of infiltrating T-cell subsets in human glioblastoma. Front Immunol; 13:850226.
  3. Tan LY, Cockshell MP, Moore E, Myo Min KK, Ortiz M, Johan MZ, Ebert B, Ruszkiewicz A, Brown MP, Ebert LM*, Bonder CS* (2022). Vasculogenic mimicry structures in melanoma support the recruitment of monocytes. OncoImmunology;11(1):2043673. * Equal senior authors
  4. Staudacher, A.H.*, Li, Y.*, Liapis, V. and Brown, M.P. (2022) The RNA-binding protein La/SSB associates with radiation-induced DNA double-strand breaks in lung cancer cell lines. Cancer Reports. Aug;5(8):e1543. doi: 10.1002/cnr2.1543. (*shared first authorship).

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. 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
  3. El Khawanky N, Hughes A, Yu W, Taromi S, Aumann K, Vinnakota MK, Clarson J, Lopez A, Brown MP, Duyster J, Hughes TP, White DL, Yong ASM, Zeiser R. Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia. Nat Comms 12(1), 6436, 2021.

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. 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)
  3. 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)  
  4. 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. 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.
  2. 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
  3. 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.
  4. 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.