Advances in the understanding of cancer immunotherapy and the development of multiple checkpoint inhibitors have dramatically changed the current landscape of cancer treatment. Recent large‐scale phase III trials (e.g. PHOCUS, OPTiM) are establishing use of oncolytic viruses as another tool in the cancer therapeutics armamentarium. These viruses do not simply lyse cells to achieve their cancer‐killing effects, but also cause dramatic changes in the tumor immune microenvironment. This review will highlight the major vector platforms that are currently in development (including adenoviruses, reoviruses, vaccinia viruses, herpesviruses, and coxsackieviruses) and how they are combined with checkpoint inhibitors. These vectors employ a variety of engineered capsid modifications to enhance infectivity, genome deletions or promoter elements to confer selective replication, and encode a variety of transgenes to enhance anti‐tumor or immunogenic effects. Pre‐clinical and clinical data have shown that oncolytic vectors can induce anti‐tumor immunity and markedly increase immune cell infiltration (including cytotoxic CD8⁺ T cells) into the local tumor microenvironment. This “priming” by the viral infection can change a ‘cold’ tumor microenvironment into a ‘hot’ one with the influx of a multitude of immune cells and cytokines. This alteration sets the stage for subsequent checkpoint inhibitor delivery, as they are most effective in an environment with a large lymphocytic infiltrate. There are multiple ongoing clinical trials that are currently combining oncolytic viruses with checkpoint inhibitors (e.g. CAPTIVE, CAPRA, and Masterkey‐265), and the initial results are encouraging. It is clear that oncolytic viruses and checkpoint inhibitors will continue to evolve together as a combination therapy for multiple types of cancers.

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.

There have been significant advances in colorectal cancer (CRC) immunotherapy over the past decade, with incorporation into both the metastatic and adjuvant/neoadjuvant treatment spaces. However, there remains a large unmet need in the CRC population, with a minority of cancers currently addressable with existing immunotherapeutic solutions. This review summarizes both our current approach and the novel therapeutics, which may soon be a part of standard practice. Current treatments focus on targeting inhibiting PD-1 and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways with antibodies, such as pembrolizumab, nivolumab, and ipilimumab. Meanwhile, there are numerous novel immunotherapeutic approaches being investigated. Recent studies have shown that Fc-enhanced PD-1/CTLA-4 antibodies can have an impact in microsatellite stable CRC. Other work has evaluated new combinatorial pathways with classic PD-1 blockade to expand response, such as LAG-3, TIGIT, and NKG2A. These treatments have been used in trials for use in metastatic CRC and in possible novel adjuvant/neoadjuvant therapies. Additional immune checkpoint inhibitor options may be incorporated into CRC trials in the near future as regimens targeting TIM-3, OX40, CD137, and VISTA, among others, have been recently investigated in advanced solid tumor trials. These approaches suggest a bright future for CRC immunotherapy with an expansion of effective immunotherapeutic options available for patients with CRC, leading to improved outcomes and quality of life.

Oncolytic viruses have emerged as a novel class of anti-cancer therapeutics with one virus already receiving United States Food and Drug Administration (FDA) approval (talimogene laherparepvec) and many others undergoing testing in clinical trials. These viruses have direct lytic effects on tumor cells as well as immunomodulatory functions to increase inflammatory cell infiltrates in the tumor microenvironment. Despite all of the advances in cancer care, pancreatic cancer remains a highly lethal malignancy. One of the main barriers to successful systemic treatment of the disease is the fibrotic tumor stroma, as the unique extracellular matrix creates an environment that promotes tumor growth and is resistant to chemotherapy and other anti-cancer agents. The pleiotropic effects of Vitamin D have been widely studied, but recent research has now demonstrated it to be an effective agent in modulating pancreatic cancer stroma to facilitate the enhanced delivery of cytotoxic chemotherapy and immunogenicity in response to treatment. This review will explore the combination of Vitamin D with oncolytic viruses and how this novel application of Vitamin D’s ability to modulate pancreatic tumor stroma may result in a potential mechanism for increasing the efficacy of oncolytic virotherapy in pancreatic cancer.