Systemic Therapy of Spontaneous Prostate Cancer in Transgenic Mice with Oncolytic Herpes Simplex Viruses

Abstract

Oncolytic viruses are an innovative therapeutic strategy for cancer, wherein viral replication and cytotoxicity are selective for tumor cells. Here we show the efficacy of systemically administered oncolytic viruses for the treatment of spontaneously arising tumors, specifically the use of oncolytic herpes simplex viruses (HSV) administered i.v. to treat spontaneously developing primary and metastatic prostate cancer in the transgenic TRAMP mouse, which recapitulates human prostate cancer progression. Four administrations of systemically delivered NV1023 virus, an HSV-1/HSV-2 oncolytic recombinant, to TRAMP mice at 12 or 18 weeks of age (presence of prostate adenocarcinoma or metastatic disease, respectively) inhibited primary tumor growth and metastases to lymph nodes. Expression of interleukin 12 (IL-12) from NV1042 virus, a derivative of NV1023, was additionally effective, significantly reducing the frequency of development of prostate cancer and lung metastases, even when the mice were treated after the onset of metastasis at 18 weeks of age. NV1042-infected cells, as detected by 5-bromo-4-chloro-3-indolyl-B-D-galactopyranoside staining for Lac Z expressed by the virus, were present in prostate tumors 1 week after the final virus injection and viral DNA was detected at 2 weeks after final virus injection by real-time PCR in primary and metastatic tumors but not in liver or blood. No toxicity was observed in any of the treated mice. The efficacy of the IL-12-expressing NV1042 virus in this aggressive prostate cancer model using a clinically relevant treatment paradigm merits its consideration for clinical studies.

Paradoxical Role of DNA Methylation in Activation of FoxA2 Gene Expression during Endoderm Development

“…We propose that upon differentiation, DNMT activation leads to CpG island methylation, which in turn causes loss of repressor protein binding. This is consistent with results showing that following dense DNA hypermethylation of promoters, EZH2 is no longer required to maintain DNA methylation and therefore is released (44). A combination of activating transcription factors that begin to be expressed in CXCR4ϩ cells, including transcription factors that activate the FoxA2 enhancer (22), together with alterations in chromatin modifications such as H3K27 trimethylation (repressive) and H3 acetylation or H3K4 dimethylation (activating) may then lead to activation of FoxA2 gene expression (Fig.…”

Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

“…Preclinical and clinical studies argue that prior immunity to HSV does not represent an obstacle. Thus, intravenously administered ␥ 1 34.5-deleted HSV was effective in prostate and pulmonary tumor models, irrespective of whether mice were previously immunized with HSV (35,36). In phase I clinical trials, ␥ 1 34.5-deleted HSV was administered i.t.…”

Concomitant Tumor and Minor Histocompatibility Antigen–Specific Immunity Initiate Rejection and Maintain Remission from Established Spontaneous Solid Tumors

“…To date, this is the first efficacious treatment for TRAMP mice at an advanced stage of disease (29,30,(33)(34)(35) and the only report of the cure of spontaneous tumors with unmanipulated, unselected donor T lymphocytes. These findings are of particular relevance in the TRAMP model in which the genetic pressure for cancer recurrence is particularly strong (11) and able to induce unresponsiveness of high-affinity tumor-specific T cells (36,37).…”