Gentile, Chiara (2021) Development and characterization of an immunotherapeutic platform based on oncolytic Herpes simplex virus and aCTLA-4 antibodies. [Tesi di dottorato]

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Abstract

In the last decade, immunotherapy has emerged as a promising approach to treat cancer. Although encouraging results have been obtained with monotherapy treatments, a large percentage of patients still do not respond, opening therapeutic options to combination of immunotherapeutics (i.e., oncolytic viruses and mAbs targeting immune checkpoints). Unfortunately, despite combination therapies emerged as a valid option thanks to synergistic efficacy, the occurrence of systemic immune-related adverse events (irAEs) often leads to treatment interruption. The purpose of my thesis was to implement a platform of immunotherapeutics based on oncolytic HSV (oHSV) encoding vectored immunomodulators for local cancer treatment. Interleukin-12 and αCTLA-4 antibody were identified as promising payloads, to be encoded within oHSV genome. The efficacy of these oHSVs was evaluated in in vivo mouse model showing significant improvement in antitumor efficacy compared to oncolytics devoid of the selected immunotherapeutic cargoes. As viral vectored αCTLA-4 antibody resulted in significant improvement of antitumor efficacy, to facilitate preclinical to clinical translation, I isolated human/murine cross-reactive αCTLA-4 antibodies through a high throughput screening of a phage display library of scFvs by Next Generation Sequencing. Additional work will explore the potential ability of the THV_CTLA4 to reduce irAEs occurrence thanks to the antibody confined expression within the TME.

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