Oncolytic viruses as immunotherapy: progress and remaining challenges

Abstract

Oncolytic viruses (OVs) comprise an emerging cancer therapeutic modality whose activity involves both direct tumor cell lysis and the induction of immunogenic cell death (ICD). Cellular proteins released from the OV-lysed tumor cells, known as damage-associated molecular patterns and tumor-associated antigens, activate dendritic cells and elicit adaptive antitumor immunity. Interaction with the innate immune system and the development of long-lasting immune memory also contribute to OV-induced cell death. The degree to which the ICD component contributes to the clinical efficacy of OV therapy is still unclear. Modulation of a range of immune interactions may be beneficial or detrimental in nature and the interactions depend on the specific tumor, the site and extent of the disease, the immunosuppressive tumor microenvironment, the OV platform, the dose, time, and delivery conditions, as well as individual patient responses. To enhance the contribution of ICD, OVs have been engineered to express immunostimulatory genes and strategies have been developed to combine OV therapy with chemo- and immune-based therapeutic regimens. However, these approaches carry the risk that they may also be tolerogenic depending on their levels and the presence of other cytokines, their direct antiviral effects, and the timing and conditions of their expression. The contribution of autophagy to adaptive immunity, the ability of the OVs to kill cancer stem cells, and the patient’s baseline immune status are additional considerations. This review focuses on the complex and as yet poorly understood balancing act that dictates the outcome of OV therapy. We summarize current understanding of the OVs’ function in eliciting antitumor immunity and its relationship to therapeutic efficacy. Also discussed are the criteria involved in restraining antiviral immune responses and minimizing pathology while promoting antitumor immunity to override immune tolerance.

Evaluation of Newcastle disease virus mediated dendritic cell activation and cross‐priming tumor‐specific immune responses ex vivo

“…The therapeutic effect of OVs is mediated through several mechanisms, including direct tumor cell lysis and activation of tumor‐specific immunity . Tumor cell lysis induced by virus infection releases tumor‐associated antigens (TAAs), immunostimulatory intracellular molecules such as danger‐associated molecular pattern molecules (DAMPs), and proinflammatory cytokines to reverse the immunosuppressed tumor microenvironment and mount antitumor immunity …”

Inhibitory Receptors Induced by VSV Viroimmunotherapy Are Not Necessarily Targets for Improving Treatment Efficacy

“…1 There is now considerable evidence that the ability of oncolytic virotherapy to control local disease involves both direct viral oncolysis and multiple host-derived effectors of the innate and adaptive immune system. 2,3 Moreover, we, and others, have focused on understanding how systemically delivered viral therapies may be used to mount a systemic anti-tumor response against widely disseminated metastatic disease, a major challenge to effective cancer therapy.…”

“…4 Additionally, the oncolytic activity of VSV engaged both adaptive and innate immune responses that contributed significantly to anti-tumor effects, which have been validated in a variety of models. 3 We, and others, have expanded the concept of oncolytic virotherapy as an immune stimulant against disseminated malignancy by showing that systemic treatment with VSV expressing a defined tumor associated antigen (such as OVA or gp100) activated adoptively transferred naive antigen specific T cells in vivo and led to effective therapy. 5 Taken together, these results demonstrate that oncolytic viruses can generate significant therapy against tumors by various mechanisms including direct oncolysis, stimulation of anti-tumor innate immunity, and activation of adaptive T cell responses against both the virus itself and tumor-associated antigens.…”

Untitled

“…The MV-NIS is injected into the tumor bed or subarachnoid space. Oncolytic viruses work by taking advantage of selective viral replication and killing in cancer cells that do not possess the cellular repair mechanisms of normal cells [26]. This selective killing also induces a systemic anti-tumor immune response.…”