Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

Abstract

Malignant melanoma, an aggressive form of skin cancer, has a low five-year survival rate in patients with advanced disease. Immunotherapy represents a promising approach to improve survival rates among patients at advanced stage. Herein, the aim of the study was to design and produce, by using engineering tools, a novel oncolytic adenovirus AdV-D24- inducible co-stimulator ligand (ICOSL)-CD40L expressing potent co-stimulatory molecules enhancing clinical efficacy through the modulation of anti-cancer immune responses. Firstly, we demonstrated the vector’s identity and genetic stability by restriction enzyme assay and sequencing, then, by performing in vitro and in vivo pre-clinical studies we explored the anti-cancer efficacy of the virus alone or in combination with anti PD-1 inhibitor in human melanoma cell lines, i.e., MUG Mel-1 and MUG Mel-2, and in immunocompetent C57BL/6 melanoma B16V mouse model. We showed that both monotherapy and combination approaches exhibit enhanced anti-cancer ability and immunogenic cell death in in vitro settings. Furthermore, AdV-D24-ICOSL-CD40L combined with anti PD-1 revealed a fall in tumor volume and 100% survival in in vivo context, thus suggesting enhanced efficacy and survival via complementary anti-cancer properties of those agents in melanoma therapy. Collectively, the novel oncolytic vector AdV-D24-ICOSL-CD40L alone or in combination with anticancer drugs, such as check point inhibitors, may open novel therapeutic perspectives for the treatment of melanoma.

Polymer Coated Oncolytic Adenovirus to Selectively Target Hepatocellular Carcinoma Cells

“…The vector was generated and amplified using standard adenovirus preparation techniques [ 37 , 38 ]. Briefly, the Ad5 WT virus was used as a backbone for the construct (Genbank #AY339865), and the following genetic modifications were made: (i) deletion of 24 bp in the E1A conserved region, (ii) insertion of the inducible costimulatory ligand (ICOSL) [ 39 , 40 ] was placed under the exogenous promoter in the E3 region. Additionally, the fiber knob was modified (AdV5/3 chimeric).…”

Novel Insights Into Mesothelioma Therapy: Emerging Avenues and Future Prospects

“…In fact, the levels of IFN-g, IL-2, and TNF-a in the pleural fluid increased after viral administration in 8 patients out of 11, thus suggesting a direct correlation with the induction of meaningful antitumor immunity (109). Oncolytic virotherapy is a rapidly growing field of immunotherapy that has been studied across a broad spectrum of malignancies (103,(110)(111)(112)(113). Mesothelioma is a good candidate for studying oncolyses, given its frequently localized pattern of growth and location.…”

Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter

“…The immunosuppressive TME favoring melanoma ICI resistance can be taken advantage of as a target for viral attack; dysfunctional immune signaling allows genetically engineered non-pathogenic viruses to selectively target cancer cells and consequently replicate in them to a greater extent than in normal cells ( 28 , 31 ). OVTs have been associated with activation of T and NK cells, release of immunogenicity stimulating agents, release of tumor-specific antigens for APC uptake, type I IFN signaling, and major histocompatibility complex (MHC) upregulation ( 32 , 33 ). The overall response rate to T-VEC monotherapy is only around 25% ( 34 ), but the true promise of OVTs arguably lies in their immunomodulatory properties.…”

“…Tumor adenovirus OVT injection drastically alters the immune landscape with increased NK, T cell and APC migration occurring. Interestingly, initial trials observed that OVTs were associated with an increase of PD-1 and PD-L1 expression ( 32 ). In response to these findings, recent reports reveal PD-L1 expression is an adaptive mechanism used by melanoma to generate OVT resistance ( 33 , 35 ).…”