Chimeric Oncolytic Adenovirus Armed Chemokine Rantes for Treatment of Breast Cancer

Abstract

The immunosuppressive state in the tumor microenvironment (TME) of breast cancer makes it difficult to treat with immunotherapy. Oncolytic viruses not only lyse tumor cells but also reshape the TME. Therefore, they can play a multi-mechanism synergistic effect with immunotherapy. In this study, an oncolytic adenovirus Ad5F11bSP-Rantes was constructed and used as a vector to express the chemokine Rantes. The objective of this study was to test the dual mechanisms of the oncolytic effect mediated by virus replication and the enhanced anticancer immune response mediated by Rantes chemotaxis of immune cells. It was found that Ad5F11bSP-Rantes has strong infectivity and effective killing activity against breast cancer cells. In the established triple negative breast cancer (TNBC) xenograft model in NCG mice whose immune system was humanized with human peripheral blood mononuclear cells (PBMCs), Ad5F11bSP-Rantes achieved 88.33% tumor inhibition rate. Rantes expression was high in mouse blood, a large number of CD3+ lymphocytes infiltrated in tumor tissues and E-cadherin was up-regulated in cancer cells, suggesting that Ad5F11bSP-Rantes altered the TME and induced a reversal of cancer cell epithelial–mesenchymal transition (EMT). In conclusion, oncolytic adenovirus can exert the oncolytic effect and the chemotactic effect of immune cells and realize the synergy of multiple anticancer effects. This strategy creates a candidate treatment for the optimization of breast cancer, especially TNBC, combination therapy.

Oncolytic viruses-modulated immunogenic cell death, apoptosis and autophagy linking to virotherapy and cancer immune response

“…The report contributes to the understanding of the molecular mechanism of ORFV oncolysis and contributes to the development of new therapies for lung cancer ( Wang et al., 2022 ). The immunosuppressive state of the breast cancer TME makes it difficult to treat with immunotherapy, but the chimeric oncolytic adenovirus armed with the chemokine regulated after activation, expressed and secreted by normal T cells (RANTES)/CC chemokine ligand 5 (CCL5) appears to be a promising drug candidate for the treatment of breast cancer ( Ang et al., 2022 ).…”

“…Additionally, OVs-mediated apoptosis may trigger anticancer immune responses in TME ( Ma et al., 2020 ). OV immunotherapy began in the 1950s when the virus was thought to invade and destroy cancer cells ( Gebremeskel et al., 2021 ; Ang et al., 2022 ; Ripp et al., 2022 ). More recently, OVs have been at the forefront of cancer immunotherapy.…”

Triple-Negative Breast Cancer: Basic Biology and Immuno-Oncolytic Viruses

“…Finally, a chimeric ADV has also been constructed to be tested as an oncolytic against TNBC. A chimeric virus between type 5 ADV and type 11b ADV was produced and the cytokine Rantes (regulated upon activation, normal T cells expressed and presumably secreted, also known as CCL5) was inserted into the E3 region of the viral genome [ 123 ]. The chimeric and recombinant Ad5F11bSP-Rantes was tested against a panel of TNBC cell lines in vitro and then trialed in an NCG mouse xenograft model bearing MDA-MB-231 tumors.…”

Construction and application of adenoviral vectors

“… 250 RANTES enhances tumor infiltration and maturation of APCs in vivo hepatocellular carcinoma Ang et al. 251 ; Li et al. 252 Bispecific T cell engager T cell activation, upregulation of proinflammatory cytokines prostate cancer Li et al.…”