The Oncolytic Virus dl922-947 Triggers Immunogenic Cell Death in Mesothelioma and Reduces Xenograft Growth

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure that urgently requires effective therapeutic strategies. Current treatments are unable to increase significantly patient survival, which is often limited to <1 year from diagnosis. Virotherapy, based on the use of oncolytic viruses that exert anti-cancer effects by direct cell lysis and through the induction of anti-tumor immune response, represents an alternative therapeutic option for rare tumors with limited life expectancy. In this study, we propose the use of the adenovirus dl 922-947, engineered to allow selective replication in cancer cells, to counteract MPM. Methods: We performed a thorough preclinical assessment of dl 922-947 effects in a set of MPM cell lines and xenografts. Cytotoxicity of dl 922-947 alone and in combination assays was evaluated by sulforhodamine B assay. Cell cycle, calreticulin expression, and high mobility group box protein 1 (HMGB1) secretion were determined by flow cytometry, whereas ATP content was determined by a luminescence-based bioassay. The modulation of angiogenic factors in MPM-infected cells was evaluated through ELISA. Results: We found that dl 922-947 infection exhibits cytotoxic effects in MPM cell lines, affecting cell viability, cell cycle progression, and regulating main hallmarks of immunogenic cell death inducing calreticulin surface exposure, HMGB1 and ATP release. Our results also suggest that dl 922-947 may affect angiogenic signals by regulation of VEGF-A and IL-8 secretion. Furthermore, dl 922-947 shows anti-tumor efficacy in murine xenograft models reducing tumor growth and enhancing survival. Finally, the combination with cisplatin potentiated the cytotoxic effect of dl 922-947. Conclusions: Overall our data identify virotherapy, based on the use of dl 922-947, as a new possible therapeutic strategy against MPM, which could be used alone, in combination with standard chemotherapy drugs, as shown here, or other approaches also aimed at enhancing the antitumoral immune response elicited by the virus.

Tumor-Associated Macrophage Status in Cancer Treatment

“…The use of virotherapy is emerging as a valid therapeutic treatment for several type of cancer. It is based on the use of OVs that, beyond their direct lytic effect on tumor cells, function through a multitude of events like modification of the tumor micro/macro-environment, modulation of the antitumor immune response [6][7][8][9]. The role of macrophages on virotherapy efficacy varies according to the tumor model.…”

“…Additionally, TAMs are mainly responsible for resistance to well-known antitumor treatments like chemotherapy and radiotherapy, indeed they limit the efficacy of immunotherapy, i.e., anti-PD1 treatment [3][4][5]. However, depending on the tumor type and treatment adopted it might be possible to identify novel approaches, i.e., combinatory therapies also taking advantage of more recent treatments as those based on the use of oncolytic viruses (OV) [6][7][8][9]. In this review, we will highlight TAMs as therapeutic target and their modulation by anticancer therapies.…”

Immunology of Adenoviral Vectors in Cancer Therapy

“…While OAd induction of ICD has not yet been confirmed, OAds are known to induce anti-tumor adaptive immune responses 55 . Di Somma et al 56 . demonstrated that an OAd dl 922-947 induces hallmarks of ICD, including surface calreticulin, HMGB1, and ATP release in infected human malignant pleural mesothelioma cell lines, resulting in tumor control and prolonged survival in xenograft models.…”

Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the dl922-947 Oncolytic Virus in Malignant Mesothelioma Cell Lines

“…Considering that virotherapy-based approaches have recently found a successful application in the clinical setting for different cancer types [ 8 , 9 , 10 ] and given that MM is a good candidate for this strategy because the pleural location provides direct access for the intra-tumoral injection of the virus [ 11 ], we have recently assessed the effects of a selectively replicating oncolytic virus (OV) in MM cell lines and murine xenografts [ 12 ]. We used, in particular, the adenovirus dl922-947 , the efficacy of which has previously been shown by our group and others in cells from different tumors [ 13 , 14 , 15 , 16 , 17 ].…”

“…Since disruption of the oncosuppressive RB1 pathway is an almost universal hallmark of human cancers, including MM [ 19 , 20 ], dl922-947 can kill tumor cells, while sparing normal cells in which the RB1 pathway is functional. We showed that dl922-947 had antitumor effects in both MM cell lines and xenografts [ 12 ]. In particular, dl922-947 affected cell cycle progression, triggered immunogenic cell death, and reduced the production of pro-angiogenic factors, consistent with the ability of OVs to induce an antitumor immune response [ 21 , 22 ] and a re-shaping of the tumor microenvironment [ 23 , 24 ].…”