Treatment of Human Pancreatic Cancers Following Local and Systemic Administration of Oncolytic Adenovirus Serotype 35

Abstract

Background/Aim: Oncolytic adenoviruses (Ads) (OAds) are gaining attention as an effective remedy for pancreatic cancer. Most OAds are based on human Ad serotype 5 (Ad5) (OAd5); however, two major drawbacks of OAd5 have been reported. Expression of coxsackievirus-adenovirus receptor, a primary infection receptor of Ad5, is often decreased on malignant tumor cells, including pancreatic cancers. More than 60% of adults have neutralizing antibodies against Ad5. Previously, we developed an OAd composed of Ad serotype 35 (Ad35) (OAd35). Ad35 recognizes CD46, which is often up-regulated on pancreatic cancers. In addition, only 20% or fewer adults have anti-Ad35 neutralizing antibodies. Materials and Methods: We examined the tumor cell lysis activities of OAd35 in the four human pancreatic cancer cell lines in the presence and absence of human serum. The tumor growth suppression effects of OAd35 after local and systemic administration were evaluated in nude mice bearing human pancreatic tumors. Results: OAd35 showed higher levels of tumor cell lysis activities than OAd5 in the human pancreatic cancer cell lines AsPC-1 and BxPC-3. Although the in vitro tumor cell lysis activities of OAd5 against MIA PaCa-2 and PANC-1 cells were strongly attenuated in the presence of human serum, OAd35 mediated comparable levels of tumor cell lysis in the presence and absence of human serum. Systemic administration of OAd5 did not mediate significant growth inhibition against the subcutaneous BxPC-3 tumor. On the other hand, OAd35 significantly suppressed tumor growth. Conclusion: OAd35 would be suitable as an alternative anticancer agent for pancreatic cancer.Pancreatic cancer is the fourth leading cause of cancerrelated death (1, 2). The 5-year survival rates are about 10% for all stages combined and 15-20% for surgically resected patients (3-6). Due to the lack of effective treatments without severe toxicity profiles, the 5-year survival rates of patients who cannot undergo surgical resection have remained unchanged (7,8). Since pancreatic cancer is often an aggressive malignancy and does not exhibit obvious symptoms, many patients present with unresectable disease or distant metastases at the time of diagnosis. The 5-year survival rate of patients with unresectable disease is less than 5%. Moreover, undetectable distant metastases make a major contribution to the low 5-year survival rate of patients undergoing surgical resection (9). Thus, there is an urgent need for the development of novel, systemically deliverable 537

Evolving Horizons: Adenovirus Vectors’ Timeless Influence on Cancer, Gene Therapy and Vaccines

“…These difficulties have pushed the scientists to look for better adenoviruses to target various cancers. For example, HAdV 35 has emerged as an alternative option for treating pancreatic cancer in a recent study [33]. Adenoviruses typically lead to respiratory problems, from the common cold to more severe conditions, such as pneumonia, croup, and bronchitis [34].…”