Oncolytic viruses for cancer immunotherapy

Abstract

In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains.As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors.Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.

Keywords: Adenovirus; Cancer; Immune system; Immunology; Immunosupression; Immunotherapy; Oncolytic; Review; Tumor.

Fig. 1

Activating the immune system for cancer rejection with oncolytic virus therapy. The tumor microenvironment of advanced cancers is “cold” due to the lack of immunological activity. Oncoytic virus therapy restores the immunological activity of immune tumor infiltrates. a Danger signal release and DC maturation. Oncolytic adenoviruses infect tumor cells and cause oncolysis, releasing new virus progeny but also DAMPS and PAMPS, which will activate nearby dendritic cells and foster their maturation by upregulating co-stimulatory markers, such as CD80, CD83, and CD86. b Mature dendritic cells will process tumor debris and present tumor-associated and virus antigens to local and distant T cells. Concurrently, the ongoing virus infection attracts T cells to the tumor site. c The activation of B cells by CD4+ T cells or BCR-virus interaction causes the release of neutralizing antibodies, which mark infected tumor cells for ADCC by NK cells, or phagocytosis by M1 macrophages. d CD8+ T cells and NK cells destroy infected and non-infected tumor cells through INFg/GranzB and GranzB/Perforins, respectively. The oncolytic adenovirus infection also upregulates class I HLA in tumor cells, allowing for increased exposure to CD8+ T cells. Overall, the components of this modulation allow the tumor microenvironment to become “hot” with increased immunological activity. DAMP danger-associated molecular patterns, PAMP pathogen-associated molecular patterns, HLA human leukocyte antigen, BCR B cell receptor