The Darcy laboratory is involved in developing novel strategies for effectively harnessing the immune system against cancer.
The goal of our laboratory is to develop effective immunotherapies for cancer. There is considerable power in the many billions of circulating blood cells that comprise the immune system. We seek to turn this disease-fighting capacity against cancer cells by using anti-cancer genes to endow immune cells with the ability to recognize and destroy tumour cells. Studies in the lab can be divided into the following main areas: (1) Strategies to enhance endogenous anti-tumor immunity (2) Combination therapies, where gene-modified immune cells are combined with reagents to overcome the tumour induced immunosuppressive microenvironment to produce the optimal anti-tumour treatment. (3) Cell selection, in which the relative anti-tumour effect of different gene-modified immune cells are examined in vivo and (4) Clinical translation, in which final preparations of genes and cells are made ready for use in clinical trials.
Adoptive immunotherapy and immunomodulators
The efficacy of targeting immune suppression pathways relies heavily on the existence of tumour-specific T cells in the immune repertoire of the tumour-bearing host. In this project we propose to utilise CAR T cells as a source of tumour-specific T cells to overcome this limitation. We were the first to show that PD-1 blockade significantly enhances the efficacy of CAR T cell therapy. Our objective is to compare the effect of blocking other checkpoint pathways (CTLA-4, TIM-3, LAG-3) on CAR T cell function in our self-antigen mouse models and in combination with immune agonists including anti-4-1BB and anti-OX-40 which are known to potently stimulate T cell immunity. These studies will also include experiments combining CAR T cells with inhibitors targeting IDO and antagonist drugs targeting the CD73/adenosine pathway. These studies will involve gaining detailed mechanistic insight into the immune pathways involved in any observed combinatorial effect and whether the combined therapy can enhance the frequency and/or function of CAR T cells trafficking to the tumour site.
Investigating the relative role of various immune subsets in adoptive immunotherapy
An effective immune response typically involves innate and adaptive immune cells but how to achieve this with CAR T cells is unclear. We have previously shown that transfer of both CD8+ and CD4+ CAR T cells produces strong anti-tumor responses in mice and demonstrated that cognate ‘help’ with IL-2 secretion by CAR+ CD4 cells was indispensible for tumor eradication. To assess the efficacy of other subsets, we have generated a transgenic mouse expressing anti-Her-2 CAR in all haematopoietic cells. For this project, we will isolate various immune cells expressing CAR to co-transfer with cognate CD8+ CAR T cells in our syngeneic, self-antigen models. Cell types of interests will include CD4 (Th1, Th2, Th9), CD8 subsets (TEM, TCM, TSCL) and innate cell populations (NK, NKT cells).
We recently completed the first-ever CAR T cell trial in Australia, targeting LeY+ AML. We demonstrated CAR T cell tracking to sites of tumour and persistence, reflecting biological responses. With PI Ben Solomon and support from US biotech Juno Therapeutics P/L (licensing agreement for access to LeY technology signed in March 2015), we now have ethics clearance and have TGA approval to commence the next CAR T cell trial in patients with LeY+ lung and other solid cancers in late 2016. Through Miles Prince and Dominic Wall, Cell Therapies P/L is undertaking all cell production and will pursue commercial opportunities that arise from our translational CAR T cell pipeline. In collaboration with Paul Neeson and David Ritchie who co-head the Hematology/Immunology Translational Research Laboratory (HITRL), we will develop new bio-markers of response and develop other potential CAR T targets and promising combination therapies for translation into patients.
*Beavis PA Henderson MA Giuffrida L et al……*Darcy PK (2016). Targeting the adenosine receptor 2A enhances the efficacy of chimeric antigen receptor (CAR) T cells. Journal of Clinical Investigation.127(3):929-941. *Corresponding authors
This study demonstrates for the first time the potential of targeting A2A mediated suppression to enhance the activity of CAR T cells, particularly against solid tumors where the activity of CAR T cells has so far been less impressive and where adenosine mediated immunosuppression is more prevalent due to the hypoxic environment.
Mardiana S, John LB et al…...*Beavis PA, *Darcy PK (2017). A multifunctional role for adjuvant anti-4-1BB therapy in augmenting anti-tumor responses by chimeric antigen receptor T cells. Cancer Research. 77(6):1296-1309. *Corresponding authors
This study demonstrates that the use of immune agonist antibodies such as α-4-1BB mAb is a viable strategy for significantly increasing therapeutic responses by CAR T cells against solid cancers.
*Beavis PA Milenkovski N et al… *Darcy PK (2015). Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced anti-tumor T cell responses. Cancer Immunology Research.3(5):506-17. *Corresponding authors
This study was the first to show that blockade of the adenosine pathway could enhance anti-PD-1 therapy through augmenting T cell responses and that expression of CD73 could be a potential biomarker for the efficacy of anti-PD-1.
Beavis PA Divisekera U et al……Darcy PK (2013). Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proceedings of the National Academy of Sciences.110(36):14711-6.
This study was the first to describe the use of adenosine receptor antagonists for blocking adenosine immunosuppression and effectively suppressing the metastasis of CD73+ tumours.
John LB Devaud C et al……Kershaw MH Darcy PK (2013). Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clinical Cancer Research.19(20):5636-46.
This study was the first to report that administration of an antibody to block PD-1 immunosuppression could significantly enhance tumour growth inhibition by CAR T cells.
Kershaw MH Westwood JA Darcy PK (2013). Gene engineered T cells for cancer therapy. Nature Reviews Cancer.13(8): 525-41.
A comprehensive review describing the latest preclinical data and clinical studies using gene-modified T cells for cancer immunotherapy.
John LB, Howland LJ et al……..Kershaw MH, Darcy PK (2012). Oncolytic virus and anti-4-1BB combination therapy elicits strong anti-tumor immunity against established cancer. Cancer Research.72(7):1651-60.*
*article was featured by Rogers SS. Combinations that work. Nat Rev Can 12(4):230, 2012.
First report demonstrating that administration of an immune activating reagent anti-4-1BB mAb could significantly enhance the efficacy of oncolytic vaccinia virus against cancer in mice.
B.Sc. (Hons) and PhD opportunities are available for students interested in the above areas. Prospective students should contact either Associate Professor Phil Darcy or Dr. Paul Beavis for details.
Associate Professor Phillip Darcy
+61 3 8559 7093
Dr. Paul Beavis
+61 3 8559 5051