Oncolytic Herpes Simplex Virus 1 Encoding 15-Prostaglandin Dehydrogenase Mitigates Immune Suppression and Reduces Ectopic Primary and Metastatic Breast Cancer in Mice

Abstract

Oncolytic human herpes simplex viruses (HSV) have been genetically engineered to limit neurovirulence and the establishment of latency and reactivation and to replicate exclusively in cells with deficient apoptotic mechanisms (i.e., cancer cells) (5, 6, 37). These genetic changes are fundamental to the safety and efficacy of oncolytic herpesviruses but often result in rapid clearance of the virus by the host immune response, thus limiting its therapeutic potential. It is precisely the antiviral immune response, however, that is thought to help overcome tumor-induced immune suppression, allowing for antitumor immunity to develop. In this regard, HSV-1 infections within tumors may function as in situ vaccines, providing the necessary inflammatory signals that engage innate and adaptive immune responses to tumor antigens. Thus, oncolytic HSV-1 may be effective both directly as a cancer killing agent and indirectly as an immunological enhancer, or in situ cancer vaccine (13,49). Previously, we reported that the novel fusogenic oncolytic herpesvirus OncSyn (OS) was effective at treating primary solid breast tumors in mice (25,26). Moreover, treatment of primary 4T1 tumors in syngeneic BALB/c mice with OS led to a substantial reduction in the formation of metastatic foci within multiple organs and in some cases eliminated lung metastasis, suggesting the development of effective antitumor immunity (43).The HSV-1 vhs gene product encoded by the UL41 open reading frame (ORF) has multiple functions that are known to suppress antiviral immune responses. (i) vhs is an RNase that degrades viral and cellular mRNAs, limiting host and viral antigen production (3,32,33,45,48,51,56,59,61,65,75). (ii) UL41 (vhs) with ICP47 is known to inhibit major histocompatibility complex I (MHC-I) antigen presentation (59), while vhs alone has also been implicated in the reduction of MHC-II expression (69). (iii) vhs has been reported to suppress production of cytokines and chemokines and inactivate dendritic cells (7,59). In agreement with these reports, deletion of the vhs gene prevented HSV-1-mediated inactivation of antigen presentation by dendritic cells (DC) (54) and improved the immunogenicity of a candidate replication-defective HSV-1 vaccine strain (16,55). Furthermore, deletion of the vhs gene causes substantial reduction in neurovirulence (48, 60, 64).

Doxorubicin-enriched, ALDHbr mouse breast cancer stem cells are treatable to oncolytic herpes simplex virus type 1

“…Although our oncolytic HSV1 can reduce the primary 4T1 tumor volume effectively, which is consistent with the previous reports [27,59,60,65,66], and decrease the frequency of ALDH br cells compared with chemotherapy, it also has its own limitations, including physical barriers such as the extracellular matrix, which restrict the initial distribution and subsequent spread of viruses in the tumor mass when the oncolytic virus is directly injected into the tumor, and anti-HSV1 immunity, which can limit virus replication when locally or systematically given repeatedly [67,68]. These limitations may be overcome by combination of viral and chemotherapies.…”

Myeloid-derived suppressor cells in murine AIDS inhibit B-cell responses in part via soluble mediators including reactive oxygen and nitrogen species, and TGF-β

“…MDSC expansion has been correlated with reduced survival among cancer patients (11). In addition to their role in inhibiting anti-tumor immunity, MDSCs have also been suggested to inhibit anti-viral immunity during influenza infection (12), murine models of chronic hepatitis B (13), vesicular stomatitis virus (14), and certain strains of herpes simplex virus (15). Conversely, a protective role for MDSCs has been reported in several autoimmune models, including collagen-induced arthritis (CIA) (16), autoimmune hepatitis (17), inflammatory bowel disease (18), and experimental autoimmune encephalomyelitis (19, 20).…”

Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration toAotusNonhuman Primates

“…A range of transgene inserts have been evaluated, including suicide genes (Chase et al, 1998;Aghi et al, 1999;Nakamura et al, 2001;Guffey et al, 2007), or those expressing antiangiogenic (Liu et al, 2006;Goodwin et al, 2012;Yoo et al, 2012), apoptotic (Han et al, 2007;Prabhakar et al, 2010), fusogenic (Nakamori et al, 2004;Simpson et al, 2009;Takaoka et al, 2011), and immunomodulatory proteins (Andreansky et al, 1998;Liu et al, 2003;Parker et al, 2005;Walker et al, 2011). Our group has focused on oHSV that express immunostimulatory cytokines (Andreansky et al, 1998;Parker et al, 2000;Hellums et al, 2005).…”