A promising approach in the treatment of different forms of cancer consists in the use of modified oncolytic viruses that carry genetic information in transformed cells to induce their own destruction. In particular, the study considered and critically analyzed in this work focuses on the ability of an engineered oncolytic virus HSV-1 (oHSV) to selectively target tumor cells and to stimulate the innate immune response of macrophages and Natural Killer cells against glioblastoma, through the expression of a full length antibody that blocks the CD47-SIRPα immune checkpoint. In fact, the intracranial administration of the oHSV virus that produces αCD47-IgG1, in addition to generating the continuous synthesis of the antibody in the intratumoral environment, is able to improve the average life of athymic mice with GBM transplant and to induce a net increase in infiltration of innate immune response cells into the tumor. Consequently, as will be discussed, the significant increase in phagocytic activity and cytotoxicity mediated by macrophages and NK cells will be related to containment and reduction of tumor growth rate.
Un approccio promettente nella cura delle diverse forme tumorali consiste nell’impiego di virus oncolitici modificati che veicolano informazioni genetiche all’interno delle cellule trasformate per indurne la distruzione. In modo particolare il lavoro preso in considerazione e analizzato criticamente in questo lavoro di Tesi focalizza l’attenzione sulla capacità di un virus oncolitico HSV-1 (oHSV) ingegnerizzato di colpire selettivamente le cellule tumorali e di attivare la risposta immunitaria innata di macrofagi e cellule Natural Killer contro il glioblastoma, mediante l’espressione di un anticorpo full lenght che agisce bloccando il checkpoint immunitario CD47-SIRPα. Infatti la somministrazione intracranica del virus oHSV che produce αCD47-IgG1, oltre a generare la continua sintesi dell’anticorpo nell’ambiente intratumorale, riesce a migliorare notevolmente la vita media di topi atimici in cui è avvenuto il trapianto del GBM e a indurre un netto aumento dell’infiltrazione delle cellule della risposta immunitaria innata nel tumore. Di conseguenza, come verrà discusso, il significativo aumento dell’attività fagocitica e della citotossicità mediata da macrofagi e da cellule NK risulterà essere strettamente correlato al contenimento e alla riduzione della velocità di crescita tumorale.
Efficacia di un virus oncolitico HSV contro il glioblastoma: come l’espressione di un anticorpo full length potenzia la risposta antitumorale di macrofagi e cellule NK
FACCHIN, ALESSIA
2021/2022
Abstract
A promising approach in the treatment of different forms of cancer consists in the use of modified oncolytic viruses that carry genetic information in transformed cells to induce their own destruction. In particular, the study considered and critically analyzed in this work focuses on the ability of an engineered oncolytic virus HSV-1 (oHSV) to selectively target tumor cells and to stimulate the innate immune response of macrophages and Natural Killer cells against glioblastoma, through the expression of a full length antibody that blocks the CD47-SIRPα immune checkpoint. In fact, the intracranial administration of the oHSV virus that produces αCD47-IgG1, in addition to generating the continuous synthesis of the antibody in the intratumoral environment, is able to improve the average life of athymic mice with GBM transplant and to induce a net increase in infiltration of innate immune response cells into the tumor. Consequently, as will be discussed, the significant increase in phagocytic activity and cytotoxicity mediated by macrophages and NK cells will be related to containment and reduction of tumor growth rate.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/34442