The Translational Cancer Immunotherapy Laboratory studies the interaction between the immune response and tumour control, with a particular emphasis on translating our ever-expanding basic science knowledge into clinically applicable therapeutic platforms. It has particular interest and expertise in bone marrow transplantation and cell and gene therapy, and is currently one of only a few centres in Australia that are conducting investigator-driven clinical trials using gene-modified T cells. In addition to developing new approaches to target cancer cells, the laboratory is also developing a method to expand donor-derived regulatory T cells to treat graft-versus-host disease, which is a common and life-threatening immune-driven complication of bone marrow transplantation. Using state-of-the-art technology, including gene-marking and single cell transcriptomics, immune reconstitution following bone marrow transplantation can be understood. Basic science research is focussed on the impact of cytomegalovirus reactivation on graft-versus-leukaemia effect. Cytomegalovirus is a common virus that is typically acquired during childhood; it has a marked influence on the immune landscape and, interestingly, has been associated with improved graft-versus-leukaemia effect following bone marrow transplantation. Our laboratory has developed a murine model of cytomegalovirus reactivation to investigate the mechanistic underpinnings of this observation, which may lead to new ways to enhance anti-leukaemic immunity.
The immune system can be effective in eliminating cancer cells and providing constant surveillance against cancer relapse. One of the earliest and most established form of cancer immunotherapy is bone marrow transplantation in which donor-derived immunity can be effective in treating otherwise incurable high-risk blood cancers. In the past decade, a number of new immunotherapeutic approaches have emerged but, whilst promising, significant challenges remain.
Team Head: Dr Siok Tey
- Dr Ping Zhang, Research Officer
- Alda Saldan, PhD student
- Raymond Au, Research Assistant
- Benjamin McEnroe, Honours Student
Selected Key Publications (Dr Tey’s full publication list can be viewed at her PubMed bibliography page):
- Epigenetic programming of T cells impacts immune reconstitution in hematopoietic stem cell transplant recipients.
Hardy K, Smith C, Tu WJ, McCuaig R, Panikkar A, Dasari V, Wu F, Tey SK, Hill GR, Khanna R, Rao S.
Blood Adv. 2018 Mar 27;2(6):656-668. doi: 10.1182/bloodadvances.2018015909.
- Eomesodermin promotes the development of type 1 regulatory T (T<sub>R</sub>1) cells.
Zhang P, Lee JS, Gartlan KH, Schuster IS, Comerford I, Varelias A, Ullah MA, Vuckovic S, Koyama M, Kuns RD, Locke KR, Beckett KJ, Olver SD, Samson LD, Montes de Oca M, de Labastida Rivera F, Clouston AD, Belz GT, Blazar BR, MacDonald KP, McColl SR, Thomas R, Engwerda CR, Degli-Esposti MA, Kallies A, Tey SK, Hill GR.
Sci Immunol. 2017 Apr 7;2(10). pii: eaah7152. doi: 10.1126/sciimmunol.aah7152.
- GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity.
Bunting MD, Varelias A, Souza-Fonseca-Guimaraes F, Schuster IS, Lineburg KE, Kuns RD, Fleming P, Locke KR, Huntington ND, Blazar BR, Lane SW, Tey SK, MacDonald KP, Smyth MJ, Degli-Esposti MA, Hill GR.
Blood. 2017 Feb 2;129(5):630-642. doi: 10.1182/blood-2016-08-734020. Epub 2016 Dec 7.
- Pharmacokinetics and immunological outcomes of alemtuzumab-based treatment for steroid-refractory acute GvHD.
Tey SK, Vuckovic S, Varelias A, Martins JP, Olver S, Samson L, Sturgeon E, Leach J, Avery J, Nakagaki M, Butler JP, Curley C, Morton AJ, Durrant ST, Kennedy GA, Hill GR.
Bone Marrow Transplant. 2016 Aug;51(8):1153-5. doi: 10.1038/bmt.2016.83. Epub 2016 Apr 4. No abstract available.
- Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice.
Wikstrom ME, Fleming P, Kuns RD, Schuster IS, Voigt V, Miller G, Clouston AD, Tey SK, Andoniou CE, Hill GR, Degli-Esposti MA.
Blood. 2015 Sep 17;126(12):1503-14. doi: 10.1182/blood-2015-01-622837. Epub 2015 Jun 30.
- Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial.
Kennedy GA, Varelias A, Vuckovic S, Le Texier L, Gartlan KH, Zhang P, Thomas G, Anderson L, Boyle G, Cloonan N, Leach J, Sturgeon E, Avery J, Olver SD, Lor M, Misra AK, Hutchins C, Morton AJ, Durrant ST, Subramoniapillai E, Butler JP, Curley CI, MacDonald KP, Tey SK, Hill GR.
Lancet Oncol. 2014 Dec;15(13):1451-9. doi: 10.1016/S1470-2045(14)71017-4. Epub 2014 Nov 14.
- Post transplant CMV-specific T-cell immune reconstitution in the absence of global T-cell immunity is associated with a high risk of subsequent virus reactivation.
Tey SK, Davenport MP, Hill GR, Kennedy GA, Durrant ST, Khanna R, Cromer D.
Bone Marrow Transplant. 2015 Feb;50(2):315-6. doi: 10.1038/bmt.2014.265. Epub 2014 Nov 17. No abstract available.
- Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo.
Zhang P, Tey SK, Koyama M, Kuns RD, Olver SD, Lineburg KE, Lor M, Teal BE, Raffelt NC, Raju J, Leveque L, Markey KA, Varelias A, Clouston AD, Lane SW, MacDonald KP, Hill GR.
J Immunol. 2013 Nov 15;191(10):5291-303. doi: 10.4049/jimmunol.1301181. Epub 2013 Oct 11.
- Autophagy mediates transporter associated with antigen processing-independent presentation of viral epitopes through MHC class I pathway.
Tey SK, Khanna R.
Blood. 2012 Aug 2;120(5):994-1004. doi: 10.1182/blood-2012-01-402404. Epub 2012 Jun 21.
- Inducible apoptosis as a safety switch for adoptive cell therapy.
Di Stasi A*, Tey SK*, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK. (*joint first author)
N Engl J Med. 2011 Nov 3;365(18):1673-83. doi: 10.1056/NEJMoa1106152.
Individualised killers – the peripheral maturation of natural killer (NK) cells
Natural killer (NK) cells mediate important anti-pathogen and anti-tumour effects. Their effectiveness in mounting these protective immune function is shaped by past infections. Cytomegalovirus (CMV), which infects 60- 80% of healthy individuals, has a particularly striking effect on NK cell maturation. We recently completed single-cell RNA-sequencing (scRNA-seq) of NK cells from patients undergoing CMV reactivation following bone marrow transplantation. The current project will use this unique set of single-cell data to investigate the changes in metabolism and acquisition of effector function during virus-driven NK cell maturation, and how these interact with the different combinations of activating and inhibitory receptors expressed by individual NK cell. This project is important because virus-driven NK cell maturation has an impact on NK cell anti-tumour efficacy and the findings can point to ways to make NK cells more effective ‘killers’ for cancer immunotherapy.
Suitable for Honours and PhD students.
Human gene-marking study – regulatory T cells to treat graft-versus-host disease (GVHD) after bone marrow transplantation
Bone marrow transplantation (BMT) can cure high risk leukaemia because the donor immune system is very effective at eradicating residual leukaemia cells. However, the donor-derived immune system can also cause tissue damage in the recipient, known as graft-versus-host disease (GVHD). Regulatory T cells (Tregs) can modulate the immune response and early phase clinical studies suggest that Tregs obtained from the bone marrow donor and infused into the recipient can help ameliorate GVHD. However, progress in the field is hampered by a lack of understanding of the fate of these Tregs after infusion because they cannot be distinguished from Tregs that are already pre-existing in the patients. Gene-marking involves the insertion of a unique DNA sequence that is integrated into the cell’s genome and passed on to all the cell’s progenies, thus enabling the infused cells and their progenies to be distinguished from endogenous non-gene-marked cells. In this world-first clinical study, we will use a form of gene-marking that enables the infused Tregs and all their progenies to be easily tracked by flow cytometry long term. This study will provide unprecedented insight into the fate of transferred Tregs in the clinical setting and whether their persistence, expansion and function can be improved with the co-administration of other drugs, such as interleukin-2. Because the infused Tregs can be readily distinguished from pre-existing Tregs, we will also be able to find out whether particular drugs have different effects on infused versus endogenous Tregs. This study is important because GVHD is a major cause of death after BMT. Furthermore, the use of Tregs is also being explored in other medical conditions including solid organ transplantation and type 1 diabetes.
Suitable for Honours and PhD students. Clinician researcher can also have a role in this project.
Show me the way – CARs redirecting T cells for cancer immunotherapy
Chimeric Antigen Receptors (CARs) are genetically engineered molecules that can redirect T cells to recognise particular antigens, such as those expressed by cancer cells. T cells that are transduced by CAR targeting CD19 have been effective in treating B cell cancers, e.g. B-cell acute lymphoblastic leukaemia and B-cell lymphoma, where conventional treatments have failed. This exciting technology is one of the major breakthroughs in cancer therapy this decade but many challenges remain. These include cancer relapse due to loss of CAR T cells, antigen escape (loss of CD19) or other as yet undefined mechanisms; life-threatening neurological adverse events and cytokine release syndrome; and lack of significant success to date with CAR T cells targeting other cancers. This project involves engineering CAR T cells for use in cancer immunotherapy.
Suitable for Honours and PhD students.
- Human gene-marking study – regulatory T cells to treat graft-versus-host disease (GVHD) after bone marrow transplantation
- Individualised killers – the peripheral maturation of natural killer (NK) cells
- Show me the way – CARs redirecting T cells for cancer immunotherapy
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