Triple Combination of Oncolytic Herpes Simplex Virus-1 Vectors Armed with Interleukin-12, Interleukin-18, or Soluble B7-1 Results in Enhanced Antitumor Efficacy

Abstract

Conditionally replicating herpes simplex virus-1 (HSV-1) vectors are promising therapeutic agents for cancer. Insertion of therapeutic transgenes into the viral genome should confer desired anticancer functions in addition to oncolytic activities. Herein, using bacterial artificial chromosome and two recombinase-mediated recombinations, we simultaneously created four ''armed'' oncolytic HSV-1, designated vHsv-B7.1-Ig, vHsv-interleukin (IL)-12, vHsv-IL-18, and vHsv-null, which express murine soluble B7.1 (B7.1-Ig), murine IL-12, murine IL-18, and no transgene, respectively. These vHsv vectors possess deletions in the c34.5 genes and contain the green fluorescent protein gene as a histochemical marker and the immunostimulatory transgene inserted in the deleted ICP6 locus. The vHsv showed similar replicative capabilities in vitro. The in vivo efficacy was tested in A/J mice harboring s.c. tumors of syngeneic and poorly immunogenic Neuro2a neuroblastoma. The triple combination of vHsv-B7.1-Ig, vHsv-IL-12, and vHsv-IL-18 exhibited the highest efficacy among all single vHsv or combinations of two viruses. Combining 1 Â 10 5 plaque-forming units each of the three armed viruses showed stronger antitumor activities than any single armed virus at 3 Â 10 5 plaque-forming units in inoculated tumors as well as in noninoculated remote tumors. Studies using athymic mice indicated that this enhancement of antitumor efficacy was likely mediated by T-cell immune responses.The combined use of multiple oncolytic HSV-1armed with different immunostimulatory genes may be a useful strategy for cancer therapy.

Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

“…Oncolytic herpes viral therapy in GBM xenografts PC Huszthy et al For GBMIII lesions in the later-effects study (Figure 3i), the median proliferative index in plaques was 16 10.73). The noninfected regions in vector-treated animals had significantly higher proliferation rate than the levels found in saline-injected control animals (Po0.001), indicating a possible compensatory response to the reduced proliferation in plaques.…”

“…7 Therefore, subsequent developments of HSV-1-based glioma therapy have focused on ways to enhance antitumor efficacy. 8 Two main strategies have been followed: modifying the vectors by deleting the immunoattenuating genes coded for by the virus, to allow enhanced immunorecognition of vector-infected cells, 9 or, by inserting immunostimulatory or therapeutic transgenes, [10][11][12][13] as well as by combining the vectors with other clinical treatment forms such as chemotherapy 14 or irradiation. 15 In neuro-oncology, the validity of experimental data obtained from preclinical evaluation of potential clinical therapies has been compromised by the widespread use of tumor-cell-line-based animal models.…”

Use of Reverse Genetics to Enhance the Oncolytic Properties of Newcastle Disease Virus

“…18) expressed from vaccinia virus or GM-CSF (19) expressed from herpes simplex virus] has shown great promise in clinical trials. In addition, preclinical reports of other viruses modified to express cytokines were able to confer an increase in their therapeutic efficacy in several tumor models (20)(21)(22)(23)(24)(25)(26)(27). In this regard, we developed several NDV vectors carrying GM-CSF, tumor necrosis factor (TNF)-a, IFN-g, or IL-2 and tested them for increased therapeutic efficacy.…”

“Armed” oncolytic herpes simplex viruses for brain tumor therapy

“…Using the HSVQuik system, we also created oncolytic HSV-1 armed with IL-12, IL-18 or soluble B7-1. 19 All of these armed HSV-1 demonstrated replicative capabilities similar to the parental virus in vitro. The in vivo efficacy was tested in A/J mice harboring subcutaneous tumors of syngeneic and poorly immunogenic Neuro2a neuroblastoma.…”