Deciphering Immune Reactivities and Regulatory Contexture in Brain Tumours to Advance the Development of Novel Immunotherapies.

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumour with a median overall survival of less than one year.

Standard treatment with surgical resection followed by concomitant radiotherapy and administration of the alkylating agent temozolomide only modestly improves survival to up to 15 months.

Following the success of cancer immunotherapy observed first in melanoma patients and in other malignancies, a significant amount of enthusiasm grew around the prospect of them delivering breakthrough impact against GBM.

However, the same immune modulatory agents showing promise against melanoma (Anti-CTLA-4 and anti PD1 antibodies) failed to demonstrate clinical benefit when evaluated in late stage GBM patients previously treated with radiation and temozolomide.

Lack of responses have been attributed to multiple causes, including poor immunogenicity of GBM tumours, however a series of new studies support the notion that the immune system can be mobilised against GBM, and that immune modulatory and vaccine agents are able to induce tumour-reactive T cell responses that infiltrate and impact GBM's tumor microenvironment (TME).

Despite these data, clinical responses to immunotherapy remain absent in GBM, stressing the need to better understand this malignancy and its interplay with the immune system to inform the development of effective immunotherapies.

Through access to tumour samples from GBM patients ,novel validated mouse models of GBM and, an established ex-vivo human GBM patient-derived tumour fragment (PDTF) platform for systematic testing of current and novel immunotherapies we will: (i) Map the T cell reactive landscape against human GBM, defining the classes of antigen (private of shared) recognised by T cells (ii) Determine the most relevant intrinsic and extrinsic pathways regulating the activity of tumour reactive T cells. (iii) Validation of high therapeutic potential targets in novel mouse models of cancer and patient derived tumour fragment models.

The identification and characterisation of the T cell reactive landscape in GBM will inform the development of personalised and non-personalised vaccine and cell therapy approaches, whilst the understanding of regulatory networks and their potential therapeutic value will deliver novel targets for the development of immunemodulatory agents and for the enhancement of the activity of cell therapies against GBM.