The impact of therapy on T-cell recognition of mutated tumour neo-antigens

Robinson, BWS., Nowak, AK., Millward, M., Creaney, J., Holt, R., Watson, M., Waddel, N., Chee, J., Newell, E.

Funding: NHMRC (2018-2020)

Synopsis: Cancer is caused by mutations which should be ‘seen’ and destroyed by the patient’s immune cells, similar to how immune cells protect us against viruses. But they don’t. This grant will study how current cancer treatments help the immune cells ‘see’ these mutations. We will undertake these studies in the important cancers lung cancer and mesothelioma

Scientific synopsis: Anti-cancer immunity targeting mutations (‘neo-antigens’): Cancer cells carry many mutations which should be ‘seen’ by the immune system as foreign and attacked by the host anti-cancer T cells. Failure of such a response may explain why most patients are not cured by modern checkpoint blockade immunotherapies. In mouse cancer models, combining immunogenic chemotherapy with immunotherapies, induces spectacular responses, augmenting neo-antigen responses and curing otherwise incurable advanced tumours. To date, clinical studies are lacking. In patients with thoracic malignancies (lung cancer and mesothelioma), we aim to;

#1: Examine the effect of chemotherapy on T cell responses to tumour neo-antigens, specifically:

1.1: the magnitude and/or range of specific T cell responses at baseline

1.2: the extent to which these baseline responses are altered by chemotherapy

#2: Characterise new neo-antigens induced by chemotherapy, examining

2.1: clonal and sub-clonal mutations/neo-antigen profiles induced by chemotherapy

2.2: host T cell responses to these chemotherapy-induced neo-antigens

We will utilise next generation sequencing and bioinformatics to identify candidate neo-antigens in human tumour cells. Cutting edge methods, including single cell studies, UV multimer exchange screening, T-cell receptor mapping will be used to explore T cell responses. The dynamic relationship between cancer therapy, the host immune system and neo-antigen generation, including analysis of sub-clonal neo-antigen bearing tumour cells will be examined in sequential samples.

For the first time we will be able to determine if, how and when chemotherapies boost specific anti-cancer immunity in humans. From a translational point of view, we will be able to monitor host specific anti-tumour responses and determine when to change therapy.

NCARD Research Team:

Bruce Robinson, Alec Redwood, Jenette Creaney, Ian Dick, Jon Chee, Ebony Rouse, Peter Chiang

Students: Linda Ye