Current Immunotherapeutic Strategies to Enhance Oncolytic Virotherapy

Abstract

Oncolytic viruses (OV) represent a promising strategy to augment the spectrum of cancer therapeutics. For efficacy, they rely on two general mechanisms: tumor-specific infection/cell-killing, followed by subsequent activation of the host's adaptive immune response. Numerous OV genera have been utilized in clinical trials, ultimately culminating in the 2015 Food and Drug Administration approval of a genetically engineered herpes virus, Talminogene laherparepvec (T-VEC). It is generally accepted that OV as monotherapy have only modest clinical efficacy. However, due to their ability to elicit specific antitumor immune responses, they are prime candidates to be paired with other immune-modulating strategies in order to optimize therapeutic efficacy. Synergistic strategies to enhance the efficacy of OV include augmenting the host antitumor response through the insertion of therapeutic transgenes such as GM-CSF, utilization of the prime-boost strategy, and combining OV with immune-modulatory drugs such as cyclophosphamide, sunitinib, and immune checkpoint inhibitors. This review provides an overview of these immune-based strategies to improve the clinical efficacy of oncolytic virotherapy.

Keywords: GM-CSF; cyclophosphamide; immune checkpoint; immune therapy; oncolytic virus; prime boost; sunitinib.

Figure 1

Oncolytic virus (OV)-mediated tumor cell lysis. (A) OV can specifically infect cancer cells, and subsequent replication can induce oncolysis. The release of tumor antigens has the potential to activate a systemic antitumor immune response. (B) The immune response induced by OV can be improved through several strategies. The prime-boost approach utilizes one priming viral platform carrying tumor-specific antigens, while a second platform—usually an OV—carrying the same antigens boosts the resultant antitumor immune response. The insertion of transgenes, such as GM-CSF, can facilitate antigen presentation on the surface of dendritic cells, and thus augment an antitumor response by recruiting natural killer (NK) cells and inducing tumor-specific cytotoxic T-cells. Immune checkpoint inhibitors can function both at the level of the tumor, targeting the programmed cell death protein 1 (PD-1) axis or peripherally at the level of the lymph nodes by targeting the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) axis. Both approaches ultimately improve the antitumor response. Immunomodulatory drugs such as sunitinib and cyclophosphamide can augment the antitumor immune response of OV by inhibiting immunosuppressive populations, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), respectively.