Sasso, Emanuele (2017) Generation and in vitro characterization of cancer immunotherapeutics based on oncolytic viruses and immune checkpoint inhibitors. [Tesi di dottorato]

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Abstract

In the last decade, advances in cancer immunotherapy, in all its facets, have revolutionized the way to treat cancer, becoming by now a pillar in the field of oncology. Immune checkpoint antibodies anti PD-1, PD-L1 and CTLA4 are successfully used in multiple types of cancer also as first-line therapy. Nevertheless, many patients do not respond to treatment or fall in continual relapse, which implies the need to boost anti-cancer immune response. Oncolytic viruses are a promising class of drug that counteract cancer both directly through cell lysis, and indirectly through recruitment of immune cells into the immunosuppressed tumour microenvironment. The clinical outcomes of recently approved Imlygic (Talimogene laherparepvec T-Vec) demonstrated, in a limited percentage of patients, an immune mediated anti-tumour effect. Thus, as confirmed by preclinical and clinical evidences, the combination of immune checkpoint modulators and oncolytic viruses could represent a breakthrough in cancer immunotherapy field. The purpose of this study was to generate cancer immunotherapeutics based on next-generation oncolytic viruses, and a large repertoire of monoclonal antibodies targeting the main immune checkpoints. I generated a HSV-1 based OV with enhanced safety in normal cells and remarkable virulence in tumour cell lines. In a complementary manner, I isolated a large repertoire of hundreds of monoclonal antibodies through an ex vivo/in silico High Throughput Screening a of phage display library of human scFvs based on Next Generation Sequencing. This strategy allowed me to rapidly identify biological active mAbs targeting immune checkpoint modulators. Additional work will explore, in vivo, the most suitable combinations of engineered oncolytic viruses with immunomodulatory mAbs from our repertoire, in preclinical settings of investigation.

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