Boosting Antigen Targeted Therapy Against Cancer (ATTAC)
Honours 2018
Supervisor(s): Professor Bruce Robinson, Drs Jon Chee and Vanessa Fear, Prof Jenette Creaney.
Location: School of Medicine, Level 5, QQ Block, Sir Charles Gairdner Hospital
Background and description of project (half a page):
Cancer cellscarry many mutations which should be ‘seen’ by the immune system as foreign (known as ‘neo-antigens’) and be attacked by the host anti-cancer CD8 T cells [cytotoxic T lymphocytes (CTL)]. There is evidence that this happens when modern checkpoint blockade (CPB) immunotherapies induce tumour regression – they are thought to ‘unleash’ anti-tumour CTLs. However such therapies, although revolutionising current cancer therapy, are only effective in a minority of patients2, possibly because the anti-tumourresponse to the patient’s neo-antigens is weak and needs boosting3 - without this boosting the CPB therapies have nothing to ‘unleash’.
One powerful way to potentially augment anti-tumour responses and thus turn the majority of non-responding patients into responders is by identifying the mutations and create vaccinestargeting those precise mutations with the goal of forcing the immune system to mount a strong attack against the tumour. Importantly, because this immune response will be directed solely at the tumour cells (unlike current checkpoint blockade immunotherapies), there should be very few if any side effects – analogous to ‘laser-guided attack’ without any ‘collateral damage’.
This project in murine models will studytumour neo-antigens,identified using gene sequencing and bioinformatics, and determine if they are recognised by the immune system (immunoassays) and how best to use them in vaccines to eradicate tumour growth.
It would be an ideal platform for a PhD and provides training in tumour immunology, bioinformatics and immunotherapy in a large group with a track record of NHMRC success and excellent supervision and training.
Hypothesis: Checkpoint blockade therapy with antiCTLA4 but not antiPD1, and immunogenic chemotherapy, will both boost neo-antigen based anti-cancer vaccine strategies.
AIM 1: To determine if checkpoint blockade therapy with antiCTLA4, antiPD1 and antiGITR boost neo-antigen based anti-cancer vaccines.
AIM 2: To determine if immunogenic chemotherapies boost neo-antigen based anti-cancer vaccine efficacy.
Translational relevance: This study may provide personalised cancer vaccine combination treatments for many cancers.
Refs: 1] Chee J et al. Immunotherapy for lung malignancies from gene sequencing to novel therapies. 2017 Chest. 151 (4), 891-7, 2] Creaney J et al. Strong spontaneous tumour neo-antigen responses to tumors induced by a natural human carcinogen. OncoImmunology. 2015 May 4:7 e1011492-1.