The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

Abstract

The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.

Genetic Modifications That Expand Oncolytic Virus Potency

“…The latter encodes the large subunit of the viral ribonucleotide reductase, a key enzyme for DNA synthesis. The combination of both deletions permits replication in tumor cells while preventing a productive infection in normal tissue ( Mineta et al, 1995 ; Uche et al, 2021 ). Patient-derived xenograft studies in nude mice showed that pediatric brain tumors are particularly sensitive to G207 ( Friedman et al, 2018 ).…”

“…Several OVs have progressed to human trials and even achieved FDA approval for specialized use in patients ( Fukuhara et al, 2016 ; Cook and Chauhan, 2020 ; Macedo et al, 2020 ). For example, the herpes viruses T-VEC, G207 and G47Δ ( Rider et al, 2019 ; Uche et al, 2021 ); the adenovirus DNX-2401 or Tasadenoturev ( Ene et al, 2021 ) and Oncorine ( Liang, 2018 ); the reovirus pelareopep ( Müller et al, 2020 ); the vaccinia virus Olvi-Vec ( Manyam et al, 2021 ); and the coxsackievirus CAVATAK ( Annels et al, 2019 ). However, many articles and reviews have reiterated that OVs developed thus far are insufficient as a monotherapy.…”

Utility of a Recombinant HSV-1 Vaccine Vector for Personalized Cancer Vaccines

“…The identification of safe, and immunogenic vaccine vectors capable of inducing potent immune responses is critical to the development of anti-infectious disease and anti-cancer intervention strategies (Vance et al, 2017). Previously, we demonstrated that the novel HSV-1 (VC2) vaccine vector, can be used to induce potent anti-tumor immune responses in a mouse model of melanoma (Uche et al, 2021b). Herein, we extend our previous findings by demonstrating that VC2 can be readily adapted to promote TAA-specific immune responses capable of extending mouse survival and decreasing tumor growth rates.…”

Identification of biological processes and signaling pathways in lactate-treated cancer cells

“…In this study, Herpes simplex virus 1 infection and Rap1 signaling pathway were considered major pathways during the lactate-treated cancer cells. Oncolytic viruses such as herpes simplex virus type 1 (HSV-1) replicate in tumors and increase immunogenic cell death and induction of immunity 21 . The HSV-1 infection was shown most effective in combination with other anti-cancer agents such as PD1/L1 related immunity 22 .…”