Enhanced hyaluronidase and tumor neoepitope expression by oncolytic adenoviruses

Resumen

The oncolytic viruses (OVs) preferentially infect tumor and selectively replicate in cancer cells without harming normal tissues. OVs have been tested in clinical trials as monotherapy or combined with chemotherapy, radiotherapy, and immunotherapy. Nonetheless, the intratumoral spreading and the immune response hamper the treatment efficacy. In this thesis, these two challenges have been addressed in three separate chapters. First, VCN-01, a hyaluronidase-expressing oncolytic adenovirus, was tested in a clinical trial in pancreatic cancer patients. We assessed the immune response triggered by VCN-01 as monotherapy or in combination with chemotherapy. We reported an early anti-viral immune response induction of IL-6, IL-10, IFNγ, IDO1, IP-10, and sLAG-3 in serum, independently of chemotherapy. We found a correlation between treatment toxicity and the IL-6 and IL-10. Furthermore, the triggered anti-viral immune response such as IFNγ, sLAG-3, and neutralizing antibodies anti-Ad5 was associated with better antitumor activity in patients. The neoepitope vaccines have been tested in patients with limited clinical responses. We hypothesized that an oncolytic adenovirus (OAd) encoding for tumor neoepitopes could be a very effective vaccine platform. The expression of tumor neoepitopes may trigger immune response towards tumors, improving OAd therapy, and bypassing the limitations of current vaccines. We provided a proof-of-concept that OAds expressing tumor neoepitopes can induce immune responses against encoded neoepitopes in naïve mice. However, no antitumor activity was observed in a murine pulmonary adenocarcinoma model. Finally, VCN-01 exhibited enhanced intratumoral spreading and potent antitumor efficacy in different models due to PH20 expression. However, higher hyaluronidase activity than VCN-01 may further treatment efficacy. Higher transcription of hyaluronidase was achieved by two different strategies: after E1a via P2A (self-cleaving peptide of porcine teschovirus-1) and after fiber via splice acceptor of Ad40 long fiber. These hyaluronidase-expressing OAds also showed improved antitumor efficacy compared to VCN-01. Furthermore, we postulated that intratumoral hyaluronidase expression may enhance T cell accumulation within tumors. As hyaluronidase activity also facilitates drug delivery into the tumors, these novel hyaluronidase-expressing OAds emerged as candidates to be combined with other treatments with limited efficacy in cancers with dense stroma.