Research Program Overview
The Cancer Immunotherapy group focuses on novel therapies that enhance a cancer patient’s immune system, to enable the patient’s own T cells to target and destroy their tumour. Such approaches include chimeric antigen receptor (CAR)-T cells, bi-specific T cell engagers (BiTE) and immune checkpoint inhibitors (ICI).
Our main focus is on brain tumours, including glioblastoma and diffuse midline glioma, as well as melanoma.
The group sits within the broader research program of the Translational Oncology Laboratory, where our shared goals are to:
- Develop innovative new therapies and diagnostics for cancer
- Translate our research findings into better patient outcomes as rapidly as possible
These goals are supported by our close ties with the Cancer Clinical Trials Unit at the Royal Adelaide Hospital.
Current Research Projects
Pre-clinical development of CAR-T cell and BiTE therapies
CAR-T cell and BiTE therapies are revolutionising the treatment of certain blood cancers, which 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 and BiTE 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; testing combination therapies; 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 have two active phase 1 clinical trials testing these GD2-targeting CAR-T cells in cancer patients. In the CARPETS trial (ACTRN12613000198729) at the Royal Adelaide Hospital, GD2-CAR-T cells are administered to patients with metastatic melanoma and other treatment-resistant solid tumours. In the Levi’s Catch trial (ACTRN 12622000675729) these CAR-T cells are given to children with brain tumours through a collaboration with Prof David Ziegler at the Sydney Children’s Hospitals Network.
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, many patients receive little to no benefit, yet are still exposed to the risk of severe side effects. Using blood and tumour samples from melanoma and lung cancer 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.
Exploring the microenvironment of brain tumours
Solid tumours don’t just contain cancerous cells, but are also infiltrated with a complex network of immune cells, blood vessels and other cell types. We have a research program focussed on understanding these cellular ecosystems in brain tumour patients, using techniques including single cell RNA sequencing and high-parameter flow cytometry. These insights will allow us to optimise our immunotherapies to function optimally within challenging tumour microenvironments.
Laboratory staff
Laboratory head
Team Members
Postdoctoral Research Scientists
Research Assistants
-
Aidan Mackereth
Students
- Erica Yeo
- Bryan Gardam
- Eunwoo (Chris) Nam
- Annaliese Thompson
- Kevin He
Select Recent Publications
- 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. 10(9):e005187
- 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.
- 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
- 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.
- 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.
- Lenin S, Ponthier E, Scheer KG, Yeo ECF, Tea MN, Ebert LM, Oksdath Mansilla M, Poonnoose S, Baumgartner U, Day BW, Ormsby RJ, Pitson SM, Gomez GA (2021). A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma. Int J Mol Sci. 22(9):4322. doi: 10.3390/ijms22094322
- 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.
- 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
- 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
- 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.
- 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.
- 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
- 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.
- 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
- 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.
