From Immunosuppression to Immunomodulation - Turning Cold Tumours into Hot

Abstract

Cancer cells employ various mechanisms to evade and suppress anti-cancer immune responses generating a "cold" immunosuppressive tumour microenvironment. Oncolytic viruses are a promising tool to convert tumour immunosuppression to immunomodulation and improve the efficacy of cancer treatment. Emerging preclinical and clinical findings confirm that oncolytic viruses act in a multimodal scheme, triggering lyses, immunogenic cell death and finally inducing anti-cancer immune responses. In this paper, we tested the local administration of a novel oncolytic adenovirus AdV-D24-ICOSL-CD40L expressing co-stimulatory molecules ICOSL and CD40L to induce the production of tumour infiltrating lymphocytes to the site of injection. Subsequently, in immunocompetent mouse models, we studied possible correlation between tumour infiltrates and anti-cancer efficacy. Described results showed that the delivery of oncolytic viruses encoding immunomodulatory transgenes in combination with anti-PD1 resulted in synergistic inhibition of both melanoma and mesothelioma tumours. Importantly anti-cancer effect positively correlated with cytotoxic CD8+ tumour-infiltrating lymphocytes exerting a central role in the tumour volume control thus generating beneficial outcomes that will undoubtedly provide new insights into possible future treatment strategies to combat cancer. Altogether our findings highlight the importance of oncolytic vectors able to modulate anti-cancer immune responses that can correlate with efficacy in solid malignancies.

Novel combinatorial therapy of oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with anti PD-1 exhibits enhanced anti-cancer efficacy through promotion of intratumoral T-cell infiltration and modulation of tumour microenvironment in mesothelioma mouse model

“…( 41 ) showed that Coxsackievirus A21 (CAVATAK) synergized in anti-cancer efficacy when administered with immune CPIs. A trial assessing CAVATAK with ipilimumab resulted in 50% objective responses in melanoma patients ( 18 , 41 ). Encouraging data have been also reported in a treatment with VALO-D102, an oncolytic vector, encoding for OX40L and CD40L, used in PeptiCRAd cancer vaccine system.…”

“…Encouraging data have been also reported in a treatment with VALO-D102, an oncolytic vector, encoding for OX40L and CD40L, used in PeptiCRAd cancer vaccine system. The local administration of PeptiCRAd strongly elevated tumor-specific T-cell responses, inhibited tumor growth, and in combination with anti-PD-1, significantly improved anti-cancer effect ( 18 , 23 ). Similar data have been also reported by Hemminki lab where i.t.…”

Advances in Immunotherapy for Malignant Pleural Mesothelioma: From Emerging Strategies to Translational Insights

“…Oncolytic viruses are emerging as targeted therapy for MPM due to their ability to destroy tumor cells without affecting non-tumor cells, releasing antigens that activate T cells through dendritic cells. 76 In the case of MPM, therapy with adenoviruses, 77 poxviruses, 78 reoviruses, 79 herpesviruses, 80 and measles virus 81 is being investigated. Virotherapy is one of the most promising alternatives, with various studies showing that human MPM cells are sensitive to many oncolytic viruses through direct cell death or immunomediated mechanisms.…”

Oncolytic Adenoviruses Armed with Co-Stimulatory Molecules for Cancer Treatment

“…However, their therapeutic efficacy is not yet optimal due to weak intratumoral virion retention, virus shedding to normal healthy organs, variable infection, and replication efficacy due to the heterogeneity of cancer [ 138 ]. Therefore, the development of new and more potent oncolytic adenoviruses is in high demand [ 139 , 140 ].…”