Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

Abstract

Cancer vaccines and oncolytic immunotherapy are promising treatment strategies with potential to provide greater clinical benefit to patients with advanced-stage cancer. In particular, recombinant vaccinia viruses (VV) hold great promise as interventional agents. In this article, we first summarize the current understanding of virus biology and viral genes involved in host-virus interactions to further improve the utility of these agents in therapeutic applications. We then discuss recent findings from basic and clinical studies using VV as cancer vaccines and oncolytic immunotherapies. Despite encouraging results gleaned from translational studies in animal models, clinical trials implementing VV vectors alone as cancer vaccines have yielded largely disappointing results. However, the combination of VV vaccines with alternate forms of standard therapies has resulted in superior clinical efficacy. For instance, combination regimens using TG4010 (MVA-MUC1-IL2) with first-line chemotherapy in advanced-stage non-small cell lung cancer or combining PANVAC with docetaxel in the setting of metastatic breast cancer have clearly provided enhanced clinical benefits to patients. Another novel cancer vaccine approach is to stimulate anti-tumor immunity via STING activation in Batf3-dependent dendritic cells (DC) through the use of replication-attenuated VV vectors. Oncolytic VVs have now been engineered for improved safety and superior therapeutic efficacy by arming them with immune-stimulatory genes or pro-apoptotic molecules to facilitate tumor immunogenic cell death, leading to enhanced DC-mediated cross-priming of T cells recognizing tumor antigens, including neoantigens. Encouraging translational and early phase clinical results with Pexa-Vec have matured into an ongoing global phase III trial for patients with hepatocellular carcinoma. Combinatorial approaches, most notably those using immune checkpoint blockade, have produced exciting pre-clinical results and warrant the development of innovative clinical studies. Finally, we discuss major hurdles that remain in the field and offer some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics.

Fig. 1

Vaccinia virus life cycle. A diagram of the infected cell with an exaggerated view of the cellular compartments, including the ER (endoplasmic reticulum), CGN (cis-Golgi network), C (cis-Golgi), M (medial-Golgi), T (trans-Golgi) and TGN (trans-Golgi network), is shown. Also shown are the major stages of the viral life cycle. Following late gene expression, pro-virion forms assemble to form the IMV. The IMV targets the TGN and, following envelopment, the IEV is formed. IEVs are propelled to the cell surface by polymerization of actin filaments. Once released, the virus may remain attached to the membrane as a CEV or be released into the medium as an EEV. CEV: cell-associated enveloped virus; EEV: extracellular enveloped virus; IEV: intracellular enveloped virus; IMV: intracellular mature virus. This figure was adapted from Grosenbach DW, Hruby DE. Front. Biosci. (1998) 3:d354–364 [174] with permission

Fig. 2

A model of how immunogenic cell death (ICD) and expression of proinflammatory Th1 cytokines from an oncolytic virus (OV) lead to potent antitumor immunity. An OV selectively replicates in tumor or/and stromal cells. This leads to induction of ICD, presenting both “find me” (extracellular HMGB1 and ATP) and “eat me” signals on the cell surface (such as ecto-CRT) to phagocytes. The presented/released danger signals (DAMPs and PAMPs) activate immature DC (iDC) to become mature DC (mDC). Apoptotic bodies and cellular fragments released via ICD are engulfed by APCs, and TAAs are processed into peptides that are presented in MHC class I/II complexes in concert with costimulatory molecules to naive CD8⁺ and CD4⁺ T cells, respectively. Such activated T cells may then expand and undergo polarized differentiation predictable on additional immune-stimulatory molecules expressed by recombinant OV. This figure has been modified from our previous model [6]. HMGB1: high mobility group box 1; DAMP: damage-associated molecular pattern; PAMP: pathogen-associated molecular pattern; APC: antigen-presenting cell; TAA: tumor-associated antigen