Associate Professor Georgina Clark
The University of Sydney School of Medicine
Dr Georgina Clark is an Associate Professor in the School of Medical Sciences. She is Group Leader of Dendritic Cell Research at the ANZAC Research Institute. Dr Clark is a molecular immunologist with a special interest in the development of therapeutic monoclonal antibodies to human myeloid and dendritic cell surface molecules She was awarded her PhD from the University of Melbourne and undertook postdoctoral studies in the Nuffield Department of Surgery at the University of Oxford, UK. Following her time in the UK, Dr Clark worked In Immunology Research at the Christchurch Medical School, University of Otago, New Zealand and then moved to Brisbane where she was the first scientist employed at the Mater Medical Research Institute where she led the Immune Regulation Research Group in the Dendritic Cell Biology Theme. Together with the late Professor Derek Hart, Dr Clark established Dendritic Cell Research at the ANZAC Research Institute in 2010. She is a member of the Council for Human Cell Differentiation Molecules Council which runs the HLDA (Human Leucocyte Differentiation Antigens) Workshops and names and characterises CD molecules.
Dr Georgina Clark’s principal research interest is in developing immune therapies for cancer particularly for haematological malignancies. Dendritic cells are critical white blood cells that control our immune responses including our responses to cancers. Dendritic cells sense the microenvironment, interact with other cells through the molecules on the plasma membrane. Understanding and characterising these cell surface molecules is critical to understanding how the cells contribute to anti-tumour responses. By developing monoclonal antibodies to the cell surface molecules, we can develop antibody based immune therapies. Antibodies are amongst the fastest growing class of therapeutic biologicals.
Leucocyte Membrane Molecules
Dr Clark is particularly interested in the molecules on the plasma membranes of human leucocytes, particularly the dendritic cells and other cells of the myeloid lineage. The cell surface landscape provides clues into how each cell interacts with its environment. Regulation of immune cell surface phenotypes is crucial to directing cell interactions. Dendritic Cell Research has a long history in describing and developing unique monoclonal antibodies to the molecules on the surface of human dendritic cells including the CD300 family or immune regulatory molecules, DC activation molecules such as CD83 and the C-type lectin molecules CD205 and CD302.
Our knowledge of the DC cell surface has provided opportunities to harness the power of monoclonal antibodies to investigate the function of specific molecules – including the checkpoint inhibitors, and to use them to develop strategies for cancer immunotherapy.
Clark et al Trends in Immunology 2009, Ju et al Blood 2008, Lo et al JI 2016, Ju et al JI 2016,Abadir et al Molecular Oncology 2019,
Human Dendritic Cell Subsets
Dendritic cells orchestrate the immune response; they stimulate responses to danger signals fighting infections and dampen response to self antigen. When things go awry, DC fail to dampen a response contributing to chronic inflammation and autoimmunity to failing to recognise a neoantigen or tumor antigen resulting in cancers. Immunotherapy approaches using blood DC to vaccinate against cancers has long been thought to have great potential but the many clinical trials in a range of cancers have met limited success. DC are a rare cell population and whilst human peripheral blood provides the most easily accessible human DC, using monocytes to derive a DC like cell “in vitro” has been the preferred source of DC in most clinical trials. Our group has concentrated on understanding the blood DC populations, their sparsity and how best to enrich for them to be able to use the “gold standard” blood DC in clinical trial. We have combined our expertise of the DC cell surface landscape to help identify different functional subpopulations of DC from human blood to ensure that we know which DC population should be targeted for a therapeutic outcome.
Clark et al., Seminars in Cell and Developmental Biology 2019
Strategies to use monoclonal antibodies to DC surface molecules as therapeutics
1. DC Immunotherapy
We have developed a platform for the purification of blood DC from apheresis sample provided by patients that will allow us to trial DC immunotherapy for prostate cancer and glioma. A vaccine will be prepared from blood DC enriched from the patient’s apheresis sample and loaded with tumor antigen in the form of mRNA in a process that will take less than 24 hours. Enough vaccine will be prepared for between 5-10 doses. We are currently working to determine the best antigens to load into the DC. Tumor environments are often immunosuppressive. Combining DC vaccines with checkpoint inhibitors are predicted to enhance the efficacy of DC vaccines and we are determining the best combination.
2. Targeting DC
Whilst purifying DC is one approach to tumour immunotherapy, directly targeting antigen to a DC in vivo would have many advantages. A number of our mAbs target molecules that are expressed primarily by DC, are able to be internalised and are thus potential DC targeting mAbs. We have made chimeric versions of these mAbs to test their efficacy as antigen loading therapeutics.
Sutherland et al, Frontiers in Immunology 2021.
3. Antibody drug conjugates
Acute Myeloid Leukemia (AML) is an aggressive leukemia with poor overall survival. We have identified a number of mAbs that target molecules expressed on leukemic blast cells from a high percentage of AML patients. We are developing these mAbs into antibody drug conjugates able to deliver toxins specifically to the leukemic cells and investigating strategies to safely use these conjugates without compromising the haematopoietic system of the patient.
Abadir et al, Blood Advances, 2020;
Development of a monoclonal antibody that enables more effective and safer haematopoietic stem cell transplantation.
Understanding the immune regulatory roles of CD300e and CD300f.
Australiasian Society of Immunology
Human Cell Differentiation Molecules Council
Sydney Cancer Partners
Publications
Journals
- Mahon, K., De Bono, J., Chi, K., Clark, G., Breit, S., Brown, D., Horvath, L., Sutherland, S., Lin, H., Stockler, M., Gurney, H., et al (2024). Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer. The Prostate, 84(8), 747-755. [More Information]
- Sutherland, S., Ju, X., Silveira, P., Kupresanin, F., Horvath, L., Clark, G. (2023). CD300f signalling induces inhibitory human monocytes/macrophages. Cellular Immunology, 390. [More Information]
- Silveira, P., Kupresanin, F., Romano, A., Hsu, W., Lo, T., Ju, X., Chen, H., Roberts, H., Baker, D., Clark, G. (2022). Anti-Mouse CD83 Monoclonal Antibody Targeting Mature Dendritic Cells Provides Protection Against Collagen Induced Arthritis. Frontiers in Immunology, 13, 784528-1-784528-19. [More Information]
2024
- Mahon, K., De Bono, J., Chi, K., Clark, G., Breit, S., Brown, D., Horvath, L., Sutherland, S., Lin, H., Stockler, M., Gurney, H., et al (2024). Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer. The Prostate, 84(8), 747-755. [More Information]
2023
- Sutherland, S., Ju, X., Silveira, P., Kupresanin, F., Horvath, L., Clark, G. (2023). CD300f signalling induces inhibitory human monocytes/macrophages. Cellular Immunology, 390. [More Information]
2022
- Silveira, P., Kupresanin, F., Romano, A., Hsu, W., Lo, T., Ju, X., Chen, H., Roberts, H., Baker, D., Clark, G. (2022). Anti-Mouse CD83 Monoclonal Antibody Targeting Mature Dendritic Cells Provides Protection Against Collagen Induced Arthritis. Frontiers in Immunology, 13, 784528-1-784528-19. [More Information]
2021
- Hey-Cunningham, A., Wong, C., Hsu, J., Fromm, P., Clark, G., Kupresanin, F., Miller, E., Markham, R., McGuire, H. (2021). Comprehensive analysis utilizing flow cytometry and immunohistochemistry reveals inflammatory changes in local endometrial and systemic dendritic cell populations in endometriosis. Human Reproduction, 36(2), 415-428. [More Information]
- Sutherland, S., Ju, X., Horvath, L., Clark, G. (2021). Moving on From Sipuleucel-T: New Dendritic Cell Vaccine Strategies for Prostate Cancer. Frontiers in Immunology, 12, 641307. [More Information]
2020
- Fromm, P., Silveira, P., Hsu, J., Papadimitrious, M., Lo, T., Ju, X., Kupresanin, F., Romano, A., Hsu, W., Bryant, C., Kong, B., Abadir, E., McGuire, H., Fazekas de St Groth, B., Hart, D., Clark, G., et al (2020). Distinguishing human peripheral blood CD16+ myeloid cells based on phenotypic characteristics. Journal of Leukocyte Biology, 107(2), 323-339. [More Information]
- Vuckovic, S., Bryant, C., Lau, K., Yang, S., Favaloro, J., McGuire, H., Clark, G., Fazekas de St Groth, B., Marsh-Wakefield, F., Nassif, N., McCulloch, D., Brown, C., Larsen, S., Gibson, J., Joshua, D., Ho, P., et al (2020). Inverse relationship between oligoclonal expanded CD69- TTE and CD69+ TTE cells in bone marrow of multiple myeloma patients. Blood Advances, 4(19), 4593-4604. [More Information]
- Abadir, E., Gasiorowski, R., Silveira, P., Larsen, S., Clark, G. (2020). Is Hematopoietic Stem Cell Transplantation Required to Unleash the Full Potential of Immunotherapy in Acute Myeloid Leukemia? Journal of Clinical Medicine, 9(2), 1-15. [More Information]
2019
- Abadir, E., Gasiorowski, R., Lai, K., Kupresanin, F., Romano, A., Silveira, P., Lo, T., Fromm, P., Kennerson, M., Iland, H., Ho, P., Hart, D., Clark, G., et al (2019). CD300f epitopes are specific targets for acute myeloid leukemia with monocytic differentiation. Molecular Oncology, 13(10), 2107-2120. [More Information]
- Li, Z., Ju, X., Silveira, P., Abadir, E., Hsu, W., Hart, D., Clark, G. (2019). CD83: Activation Marker for Antigen Presenting Cells and Its Therapeutic Potential. Frontiers in Immunology, 10, 1-9. [More Information]
- Lo, T., Abadir, E., Gasiorowski, R., Kabani, K., Ramesh, M., Orellana, D., Fromm, P., Kupresanin, F., Newman, E., Cunningham, I., Hart, D., Silveira, P., Clark, G. (2019). Examination of CD302 as a potential therapeutic target for acute myeloid leukemia. PloS One, 14(5), 1-15. [More Information]
2018
- Hsu, J., Bryant, C., Papadimitrious, M., Kong, B., Gasiorowski, R., Orellana, D., McGuire, H., Fazekas de St Groth, B., Joshua, D., Ho, P., Iland, H., Gibson, J., Clark, G., Fromm, P., Hart, D., et al (2018). A blood dendritic cell vaccine for acute myeloid leukemia expands anti-tumor T cell responses at remission. OncoImmunology, 7(4), e1419114-1-e1419114-11. [More Information]
- Kim, J., Kong, B., Lo, T., Papadimitrous, M., Hsu, J., Fromm, P., Alexander, K., Buckland, M., Clark, G., Hart, D. (2018). A combinatory immunotherapy against brain tumour: blood dendritic cell based vaccine therapy with checkpoint inhibitor(s). Neuro-Oncology, 20(Suppl 6), vi94-vi95. [More Information]
- Li, Z., Ju, X., Lee, K., Clarke, C., Hsu, J., Abadir, E., Bryant, C., Pears, S., Sunderland, N., Heffernan, S., Lo, T., Fromm, P., Silveira, P., Cooper, W., Brown, C., Clark, G., Hart, D., et al (2018). CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma. Haematologica, 103(4), 655-665. [More Information]
2016
- Bryant, C., Fromm, P., Kupresanin, F., Clark, G., Lee, K., Clarke, C., Silveira, P., Suen, H., Brown, R., Newman, E., Ho, P., Bradstock, K., Joshua, D., Hart, D., et al (2016). A CD2 high-expressing stress-resistant human plasmacytoid dendritic-cell subset. Immunology and Cell Biology, 94(5), 447-457. [More Information]
- Fromm, P., Kupresanin, F., Brooks, A., Dunbar, P., Haniffa, M., Hart, D., Clark, G. (2016). A multi-laboratory comparison of blood dendritic cell populations. Clinical & Translational Immunology, 5(4), 1-9. [More Information]
- Lo, T., Silveira, P., Fromm, P., Verma, N., Vu, P., Kupresanin, F., Adam, R., Kato, M., Cogger, V., Clark, G., Hart, D. (2016). Characterization of the expression and function of the C-type lectin receptor CD302 in mice and humans reveals a role in dendritic cell migration. Journal of Immunology, 197(3), 885-898. [More Information]
2015
- Engel, P., Boumsell, L., Balderas, R., Bensussan, A., Gattei, V., Horejsi, V., Jin, B., Malavasi, F., Mortari, F., Schwartz-Albiez, R., Clark, G. (2015). CD Nomenclature 2015: Human Leukocyte Differentiation Antigen Workshops as a Driving Force in Immunology. Journal of Immunology, 195(10), 4555-4563. [More Information]
2014
- Gasiorowski, R., Clark, G., Bradstock, K., Hart, D. (2014). Antibody therapy for acute myeloid leukaemia. British Journal of Haematology, 164(4), 481-495. [More Information]
2013
- Gasiorowski, R., Ju, X., Hart, D., Clark, G. (2013). CD300 molecule regulation of human dendritic cell functions. Immunology Letters, 149(1-2), 93-100. [More Information]
2011
- Ding, Y., Ju, X., Azlan, M., Hart, D., Clark, G. (2011). Screening of the HLDA9 panel on peripheral blood dendritic cell populations. Immunology Letters, 134(2), 161-166. [More Information]
2010
- Jongbloed, S., Kassianos, A., McDonald, K., Clark, G., Ju, X., Angel, C., Chen, C., Dunbar, P., Wadley, R., jeet, V., Hart, D., et al (2010). Human CD141+ (BDCA-3 dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. The Journal of Experimental Medicine, 207(6), 1247-1260. [More Information]
2009
- Clark, G., Ju, X., Tate, C., Hart, D. (2009). The CD300 family of molecules are evolutionarily significant regulators of leukocyte functions. Trends in Immunology, 30(5), 209-217. [More Information]
- Clark, G., Ju, X., Azlan, M., Tate, C., Ding, Y., Hart, D. (2009). The CD300 molecules regulate monocyte and dendritic cell functions. Immunobiology, 214, 730-736. [More Information]
2008
- Hart, D., Clark, G., Ju, X., Zenke, M. (2008). Cd300a and Cd300c on Plasmacytoid Dendritic Cells Are down-Regulated by Tlr7 and Tlr9 Ligand Induced Type I Interferon. Biology of Blood and Marrow Transplantation, 14(2), 118-118.
- Ju, X., Zenke, M., Hart, D., Clark, G. (2008). CD300a/c regulate type I interferon and TNF-(alpha) secretion by human plasmacytoid dendritic cells stimulated with TLR7 and TLR9 ligands. Blood, 112(4), 1184-1194. [More Information]
2007
- Clark, G., Jamriska, L., Rao, M., Hart, D. (2007). Monocytes immunoselected via the novel monocyte specific molecule, CD300e, differentiate into active migratory dendritic cells. Journal of Immunotherapy, 30(3), 303-311. [More Information]
- Clark, G., Rao, M., Ju, X., Hart, D. (2007). Novel human CD4+ T lymphocyte subpopulations defined by CD300a/c molecule expression. Journal of Leukocyte Biology, 82(5), 1126-1135. [More Information]
2006
- Modra, C., Jamriska, L., Rao, M., Clark, G., Hart, D. (2006). MMRI-23: A potential role in AML antibody-mediated therapy. Blood, 108(11), 225b-225b.
2005
- Modra, C., Radford, K., Gardiner, D., Hart, D., Clark, G. (2005). An inhibitory molecule involved in myeloid and DC differentiation. Tissue Antigens: immune response genetics, 66(5), 494-494.
- Clark, G., Munster, D., Yusuf, S., Hart, D. (2005). Eighth Leucocyte DiVerentiation Antigen Workshop DC section summary. Cellular Immunology, 236, 21-28. [More Information]
- Collin, M., Munster, D., Clark, G., Wang, X., Dickinson, A., Hart, D. (2005). In vitro depletion of tissue-derived dendritic cells by CMRF-44 antibody and alemtuzumab: implications for the control of Graft-versus-host disease. Transplantation, 79(6), 722-725. [More Information]
Selected Grants
2023
- Sartorius Incucyte SX5 Live-Cell Analysis System, Kennerson M, Cogger V, Clark G, DVC Research/Equipment Grant
2017
- Therapeutic Antibody Translation into Patients, Clark G, Ho P, Larsen S, Horvath L, Cancer Institute NSW/Translational Program Grant