Coluccino, Ludovica (2025) IL-12-expressing oncolytic adenovirus armed with tumor antigens induces a robust antitumor response in melanoma and colorectal cancer preclinical models. [Tesi di dottorato]

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Abstract

Immunovirotherapy (IVT) is an emerging cancer treatment approach that uses oncolytic viruses (OVs) as therapeutic agents. OVs infect and selectively replicate in cancer cells, inducing an immunogenic cell death (ICD) consequently activating the immune system against the tumor. Despite OVs therapy excellent results in a subset of patients, inconsistent and short-term antitumor T-cell responses is often observed in the majority of patients. Arming OVs with immunostimulatory cytokines or specific tumor antigens represents a promising strategy to increase their efficacy and elicit a sustained and more efficient antitumor immune response. To achieve this, we generated and characterized an oncolytic adenoviral vector armed with interleukin-12 (Ad5/3Δ24_IL-12), a potent cytokine able to trigger a strong antitumor T-cell response. In addition, we coated Ad5/3Δ24_IL-12 with peptides derived from tumor-associated antigens (TAAs), using the PeptiCRAd platform (PeptiCRAd_IL-12); we then evaluated the anticancer efficacy of this OV in a syngeneic murine model of melanoma (B16.OVA) and colorectal carcinoma (CT26). Specifically, we generated two peptide-coated Ad5/3Δ24_IL-12 decorated with SIINFEKL and SYLPPGTSL antigens; the first antigen is expressed in B16.OVA melanoma cells, while the second antigen is expressed in CT26 colorectal carcinoma cells. PeptiCRAd_IL-12 therapy significantly reduced tumor growth in the melanoma model, compared to the control group treated with the unarmed PeptiCRAd. Furthermore, analysis of the tumor-draining lymph nodes and spleens, demonstrated that PeptiCRAd_IL-12 therapy induced a reshaping of the tumor microenvironment by promoting dendritic cell maturation and enhancing cytotoxic T-cell activity, while reducing immunosuppressive populations, such as regulatory T-cells and anti-inflammatory macrophages. Similarly, PeptiCRAd_IL-12 therapy demonstrated a pronounced immunostimulatory effect in the colorectal cancer models. We observed an increased percentage of tumor-infiltrating CD8+ T lymphocytes and a significant decrease of exhausted T-cells, supporting the critical role of IL-12 in enhancing T-lymphocytes recruitment and infiltration in the tumor. Based on our results, we have strong evidence that incorporating IL-12 expression into the PeptiCRAd system enhances antitumoral immunity in both melanoma and colorectal cancer models.

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