Interferon‐expressing oncolytic adenovirus + chemoradiation inhibited pancreatic cancer growth in a hamster model

Abstract

Past clinical trials of adjuvant therapy combined with interferon (IFN) alpha, fluorouracil, cisplatin, and radiation improved the 5‐year survival rate of pancreatic ductal adenocarcinoma (PDAC). However, these trials also revealed the disadvantages of the systemic toxicity of IFN and insufficient delivery of IFN. To improve efficacy and tolerability, we have developed an oncolytic adenovirus‐expressing IFN (IFN‐OAd). Here, we evaluated IFN‐OAd in combination with chemotherapy (gemcitabine + nab‐paclitaxel) + radiation. Combination index (CI) analysis showed that IFN‐OAd + chemotherapy + radiation was synergistic (CI <1). Notably, IFN‐OAd + chemotherapy + radiation remarkably suppressed tumor growth and induced a higher number of tumor‐infiltrating lymphocytes without severe side toxic effects in an immunocompetent and adenovirus replication‐permissive hamster PDAC model. This is the first study to report that gemcitabine + nab‐paclitaxel, the current first‐line chemotherapy for PDAC, did not hamper virus replication in a replication‐permissive immunocompetent model. IFN‐OAd has the potential to overcome the barriers to clinical application of IFN‐based therapy through its tumor‐specific expression of IFN, induction of antitumor immunity, and sensitization with chemoradiation. Combining IFN‐OAd with gemcitabine + nab‐paclitaxel + radiation might be an effective and clinically beneficial treatment for PDAC patients.

The investigation of oncolytic viruses in the field of cancer therapy

“…Expression of IFN in OVs can effectively induce tumor cell death through modulation of various pathways ( 22 ). Studies have demonstrated that oncolytic adenovirus (OAd) expressing IFN (IFN-OAd) significantly suppresses tumor growth in hamster pancreatic cancer models, leading to increased infiltration of tumor-infiltrating lymphocytes (TILs) ( 23 ). Furthermore, the incorporation of CD47 and IFNγ genes into MYXV results in the production of MYXV_IFNγ and MYXV_CD47, respectively.…”