Phillip Darcy

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.

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.