Award Title: Understanding and harnessing the antigenicity and adjuvanticity of combination oncolytic virus and targeted drug immunotherapy
Funder: Cancer Research UK

Abstract: Background: during our current programme we have investigated combination immunovirotherapy, including with targeted small molecules.  We have uncovered immune-mediated enhancement of the oncolytic viruses (OV) reovirus and herpes simplex virus (HSV), in combination with inhibitors of BRAF, poly(ADP)-ribose polymerase 1 (PARP-1) and CDK4/6.  These studies have predominantly focused on tumour cell-intrinsic immune mechanisms, including i) reovirus-mediated activation of cellular PARP1 and PARylation of cellular proteins, leading to enhanced extrinsic apoptosis dependent on nucleic acid sensing mechanisms mediated by RIG-I and TLR3, and ii) combination reovirus/palbociclib augmentation of the endoplasmic reticulum stress/unfolded protein response, leading to increased IFN signalling and endogenous retroviral transcripts.  Critically, these combination strategies did not rely on increase in viral replication, supporting the paradigm whereby OV primarily act as immunotherapy.  

Aims: this proposal builds on our OV/targeted drug data to test immunogenicity in whole animal and human multicellular models.  We propose that an increased understanding of both antigenicity and adjuvanticity, which together determine therapy, will inform better design of combination immunotherapy strategies of OV/targeted drugs for clinical testing.  To achieve this, we will elucidate the tumour associated antigens (TAA) and tumour immune microenvironment (TIME) changes which are associated with successful combination treatment. 

Methods: we will focus on melanoma and head and neck cancer, and the immunogenicity of reovirus and HSV in combination with targeted drugs.  As TAA, we will investigate i) cancer testis antigens, ii) human papilloma virus proteins, and iii) APOBEC-driven neoepitopes, as a type of neoantigen we have shown to be induced by OV.  In addition to established immune readouts of anti-tumour immune activation, we will apply and develop novel assays comprising: i) bioinformatic prediction of TAA immunogenicity using population-based, as well as class I-specific approaches, ii) measurement of epitope presentation by immunopeptidomics (direct by tumour cells and cross-presented by antigen presenting cells), and iii) functional T cell stimulation and priming assays based on predicted/presented epitopes.  Testing of therapy in mice will include application of the murine ‘Timer of cell kinetics and activity’ (Tocky) system, to elucidate temporal and dynamic changes in T cell signalling (including antigen specific), which are central to shaping a beneficial treatment response.  

How the results of this research will be used: this proposal will inform rational strategies, based on detailed mechanistic understanding, of OV/drug combinations to take forward into clinical testing.  Our integrated mouse/human antigen/adjuvant pipeline platform can also be applied for mechanistic testing of wider immunotherapy strategies.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS