Enhanced antitumoral activity of oncolytic herpes simplex virus with gemcitabine using colorectal tumor models

Abstract

To enhance the oncolytic activity of herpes simplex viruses (HSVs) control of immune-suppression and immune-resistance by cancer cells is important. Myeloid-derived suppressor cells (MDSCs), which interfere with tumor-suppressive environments, are inhibited by gemcitabine (GEM) treatment. We investigated the oncolytic activity and systemic antitumor immunity induced by oncolytic HSVs in combination with GEM treatment. A mouse model with subcutaneous tumors on both sides of the lateral flanks was used. A highly attenuated HSV type 1, strain HF10, was inoculated into one side of each tumor three times following intraperitoneal injection of GEM. Histopathological changes and IFN-c secretion of the tumor and leukocytes in the spleen were analyzed. These treatments were repeated to enhance oncolytic activity. HF10 inoculation reduced tumor growth only on the HF10-treated side. HF10 inoculation following GEM treatment resulted in greater reduction of tumor growth on the HF10-treated tumor; furthermore, reduction of tumors on the contralateral untreated side was also observed. Necrosis of the tumor was observed in areas where HSV-infected cells were detected. F4/80 1 macrophages around the tumor were eliminated, and CD4 1 T and CD8 1 T cells increased in the spleen. A single injection of GEM decreased CD11b 1 /Gr-1 1 MDSCs while retaining CD4 1 T cells and CD8 1 T cells. Repetition of this treatment regimen resulted in even greater reduction of tumor growth on both sides and complete rejection in some of the mice. Intratumoral injection of oncolytic HSVs following GEM injection reduced MDSCs. Repeated treatment with oncolytic HSVs following GEM resulted in enhanced oncolytic activity.Genetically altered, replication-competent viruses have been developed for cancer therapy, 1 as well as for gene-delivery vectors 2 and vaccine vectors. 3 The use of viruses that selectively replicate in and kill tumor cells is called oncolytic virotherapy. At present, oncolytic virotherapy is a promising anticancer therapy, as cancer-cell specific viral replication can boost therapeutic efficacy. 4,5 Herpes simplex virus (HSV) has many advantages over other viruses for oncolytic virotherapy.First, it has a broad host range and high efficiency of infection. Second, HSV can be engineered to deliver therapeutic transgenes, since it has a large genomic capacity. Furthermore, HSV can be controlled by antiherpetic drugs, such as acyclovir.HF10 is a spontaneously occurring, highly attenuated virus isolated from the HSV-1 strain HF in our laboratory. 6,7 We have been exploring the potential use of HF10 as an oncolytic agent using various tumor models. [7][8][9][10][11][12][13][14][15] In a subcutaneous tumor model of murine colorectal cancer that uses CT26 cells, oncolytic activity of HF10 was detected; however, its antitumor effect was limited. 10 In CT26 cells, tumor-associated macrophages (TAMs), which prompt tumor growth, were reported to accumulate around the tumor mass. 16 Control of immune-suppression and immune-resistance by cancer cells ...

Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus

“…As shown in Fig. 6A and B, plaques formed by KGN bearing wild-type gD were readily detected and similar in size, irrespective of cellular EGFR expression, in accordance with the reported HSV susceptibility of CT26 cells (59,60). In contrast, KGNE-BhKt developed syncytia on CT26-EGFR acceptor cells, while only single infected (presumably donor) cells or very small foci of single infected cells were detected in mock-transduced CT26 acceptor cells (Fig.…”

“…CT26 cells are susceptible to wild-type HSV and have been used by others to test the efficacy of oncolytic HSVs (59,60). CT26-EGFR cells were infected with KGN or KGNE-BhKt at an MOI of 10 to achieve 100% infection.…”

Chemotherapy and Oncolytic Virotherapy: Advanced Tactics in the War against Cancer

“…The therapeutic benefits of using these OV-drug combinations depend on several factors, including the type of OV-drug combination used, the timing, frequency, and dosage of drug administration, and the cancer type targeted. However, given that these immunomodulatory drugs have other antitumoral effects, few studies have directly assessed their ability to deplete MDSCs in each context (135, 136). Notably, use of these drugs to deplete MDSCs can also positively or negatively affect oncolytic virotherapy.…”

Oncolytic Viruses as Anticancer Vaccines

“…Myeloid suppressor cells are attractive targets for therapeutic investigations (85). Related to oncolytic virotherapy, it was shown that the combination with gemcitabine, which is a chemotherapeutic agent depleting MDSC populations, increases antitumoral immune responses (86, 87). …”