In a bench to bedside effort, researchers in the Translational Oncology Laboratory are applying advances in immunotherapeutic technologies to the treatment of melanoma, myeloid leukaemias, brain and lung cancers, which affect millions around the world. The two major technologies of interest are chimeric antigen receptors (CARs) for re-directing lymphocytes toward cancers and antibody drug conjugates (ADCs) for targeting potent cytotoxins to cancers.
We are developing pre-clinical and clinical approaches for the treatment of these cancers to aid in diagnosis, therapy monitoring and treatment. Much of our research is collaborative, working in association with the RAH Cancer Clinical Trials Unit and partnering with other laboratories within the Centre for Cancer Biology.
Chimeric Antigen Receptor (CAR) Technology
Many cancers that evade the immune system can be re-targeted successfully with genetically engineered lymphocytes or T cells. Using CAR technology, we are investigating combinations of molecules for targeting and activating T cells against common cancers. We are also interested in how CAR gene-modified T cells enter cancers, particularly via vasculogenic mimicry or ‘false’ blood vessels.
- CAR T cell therapy for metastatic melanoma: early-phase clinical trial of autologous T cell therapy directed toward the GD2 antigen, which is expressed by over half of metastatic melanoma cases.
- Pre-clinical studies of CAR T cells in animal models of leukaemia and brain cancer: investigating novel kinds of CAR T cells and how they target cancers.
Antibody Drug Conjugate 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. Non-invasive methods for detecting cancer cell death can be useful for the early evaluation of therapeutic responses.
- 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 adaptingthe APOMAB® monoclonal antibody for use in immuno-positron emission tomography (PET). A generous PhD scholarship is available to help support this work.
- Cancer Genomics Initiative: We are identifying targets across a range of cancer types for small-molecule kinase inhibitor drugs that shrink and stabilise cancer, so that more patients may be matched efficiently with the right treatment.
Brown, M.P. and G.V. Long. The Use of Vemurafenib in Australian Patients with Unresectable or Metastatic Melanoma Containing the V600 BRAF Gene Mutation. Asia-Pacific Journal of Clinical Oncology10 Suppl. 3, (in press). (2014)
Simovic, S., K. R. Diener, A. Bachhuka, K. Kant, D. Losic, J. D. Hayball, M.P. Brown and K. Vasilev. "Controlled release and bioactivity of the monoclonal antibody rituximab from a porous matrix: a potential in situ therapeutic device." Biomaterials Science (in press). (2014)
Al-Ejeh, F., M. Pajic, W. Shi, M. Kalimutho, M. Miranda, A.M. Nagrial, A. Chou, A.V. Biankin, S.M. Grimmond, A.G.P.I., M.P. Brown and K.K. Khanna. "Gemcitabine and Chk1 inhibition potentiate EGFR-directed radioimmunotherapy against pancreatic ductal adenocarcinoma." Clin Cancer Res Published OnlineFirst May 16, 2014; doi:10.1158/1078-0432.CCR-14-0048.
Brown, M.P. and A.H. Staudacher. "Could bystander killing contribute significantly to the anti-tumor activity of brentuximab vedotin given with standard first-line chemotherapy for Hodgkin Lymphoma?" Immunotherapy 6:371-375. (2014)
Larkin, J., M. Del Vecchio, P.A. Ascierto, I. Krajsova, J. Schachter, B. Neyns, E. Espinosa, C. Garbe, V.C. Sileni, H. Gogas, W.H. Miller, M. Mandalà, G.A.P. Hospers, A. Arance, P. Queirolo, A. Hauschild, M.P. Brown, L. Mitchell, L. Veronese and C.U. Blank. "Vemurafenib in BRAFV600 mutant metastatic melanoma: an open-label, multicentre safety study of 3222 patients." Lancet Oncol 15: 436-444. (2014)
Al-Ejeh, F., A.H. Staudacher, D.R. Smyth, J.M. Darby, D. Denoyer, C. Tsopelas, R.J. Hicks and M.P. Brown. "Post-chemotherapy and tumor-selective targeting with the La-specific DAB4 monoclonal antibody relates to apoptotic cell clearance." J Nucl Med 55: 772-779. (2014)
Staudacher, A.H., F. Al-Ejeh, C.K. Fraser, J.M. Darby, D.M. Roder, A. Ruszkiewicz , J. Manavis and M.P. Brown. "The La antigen is over-expressed in lung cancer and is a selective dead cancer cell target for radioimmunotherapy using the La-specific antibody APOMAB." EJNMMI Res 4: 2. DOI: 10.1186/10.1186/2191-219X-4-2. (2014)
Pishas, K.I., S.J. Neuhaus, M.T. Clayer, A.W. Schreiber, D.M. Lawrence, M. Perugini, R.J. Whitfield, G. Farshid, J. Manavis, S. Chryssidis, B.J. Mayo, R.C. Haycox, M.P. Brown, R.J. D’Andrea, A. Evdokiou, D.M. Thomas, J. Desai, D.F. Callen and P.M. Neilsen. "Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling." Cancer Res 74: 921-931. (2014)
Penfold, S.N., M.P. Brown, A.H. Staudacher and E. Bezak. "Monte Carlo simulations of dose distributions with necrotic tumor targeted radioimmunotherapy." Appl Radiat Isotopes 12: 40-45. (2014)
Shahnam, A., D.M. Roder, E.A. Tracey, S. Neuhaus, M.P. Brown and M.J. Sorich. "Can cancer registries show whether treatment is contributing to survival increases for melanoma of the skin at a population level?" J Eval Clin Prac 20: 74-80. (2014)
Eberhardt, W. E., P. Mitchell, J. H. Schiller, M. P. Brown, M. Thomas, G. Mills, V. Jehl, S. R. Urva, J. J. De Leo, S. Gogov and V. Papadimitrakopoulou. "Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non-small cell lung cancer." Invest New Drugs 32: 123-134. (2014)