Gene therapy with viral vectors has significantly advanced in the past few decades, with adenovirus being one of the most commonly employed vectors for cancer gene therapy. Adenovirus vectors can be divided into 2 groups: (1) replication-deficient viruses; and (2) replication-competent, oncolytic (OVs) viruses. Replication-deficient adenoviruses have been explored as vaccine carriers and gene therapy vectors. Oncolytic adenoviruses are designed to selectively target, replicate, and directly destroy cancer cells. Additionally, virus-mediated cell lysis releases tumor antigens and induces local inflammation (e.g., immunogenic cell death), which contributes significantly to the reversal of local immune suppression and development of antitumor immune responses (“cold” tumor into “hot” tumor). There is a growing body of evidence suggesting that the host immune response may provide a critical boost for the efficacy of oncolytic virotherapy. Additionally, genetic engineering of oncolytic viruses allows local expression of immune therapeutics, thereby reducing related toxicities. Therefore, the combination of oncolytic virus and immunotherapy is an attractive therapeutic strategy for cancer treatment. In this review, we focus on adenovirus-based vectors and discuss recent progress in combination therapy of adenoviruses with immunotherapy in preclinical and clinical studies.

Oncolytic Adenoviruses (OAds) are one of the most promising anti-cancer agents that can induce cancer specific cell death. Recently, we generated infectivity-selective OAd, and the resultant OAd tumor-specific binding shows strong efficacy and mitigates toxicity. In this study, we applied this strategy based on adenovirus library screening system for generation of CD133-targeted OAd, and examined their oncolytic activity against colorectal cancer (CRC) in vitro and in vivo. CD133 (Prominin-1) is an important cell surface marker of cancer stem (like) cells (CSCs) in various cancers, including CRC. Elimination of CSCs has a high likelihood to improve CRC treatment because CSCs population in the tumor contributes to recurrence, metastases, chemotherapy resistance, and poor survival. The OAd with CD133-targeting motif (AdML-TYML) selectively infected CD133+ cultured cells and lysed them efficiently. Treatment with AdML-TYML prior to tumor inoculation inhibited the establishment of tumor of CD133+ CRC cell lines in nude mice. AdML-TYML also showed strong antitumor effect after intratumoral injections in already established CD133+ CRC subcutaneous xenografts. Our results indicate that CD133-targeted OAd selectively infected CD133+ CRC, and exhibited anti-tumorigenicity and therapeutic effect in established tumors. This novel infectivity selective virus could be a potent tool for the prevention of metastases and relapses in CRC.

Mortality from pancreatic ductal adenocarcinoma (PDAC) has remained essentially unchanged for decades and its relative contribution to overall cancer death is projected to only increase in the coming years. Current treatment for PDAC includes aggressive chemotherapy and surgical resection in a limited number of patients, with median survival of optimal treatment rather dismal. Recent advances in gene therapies offer novel opportunities for treatment, even in those with locally advanced disease. In this review, we summarize emerging techniques to the design and administration of virotherapy, synthetic vectors, and gene-editing technology. Despite these promising advances, shortcomings continue to exist and here will also be highlighted those approaches to overcoming obstacles in current laboratory and clinical research.

Pancreatic cancer is an aggressive malignant disease and the efficacy of current treatments for unresectable diseases is quite limited despite recent advances. Gene therapy/virotherapy strategies may provide new options for treatment of various cancers including pancreatic cancer. Oncolytic adenovirus shows an antitumoral effect via its intratumoral amplification and strong cytocidal effect in a variety of cancers and it has been employed for the development of potent oncolytic virotherapy agents for pancreatic cancer. Our ultimate goal is to develop an oncolytic adenovirus enabling treatment of patients with advanced or spread diseases by systemic injection. Systemic application of oncolytic therapy mandates more efficient and selective gene delivery and needs to embody sufficient antitumor effect even with limited initial delivery to the tumor location. In this review, the current status of oncolytic adenoviruses from the viewpoints of vector design and potential strategies to overcome current obstacles for its clinical application will be described. We will also discuss the efforts to improve the antitumor activity of oncolytic adenovirus, in in vivo animal models, and the combination therapy of oncolytic adenovirus with radiation and chemotherapy.