Brain Tumor Oncolysis with Replication-Conditional Herpes Simplex Virus Type 1 Expressing the Prodrug-Activating Genes, CYP2B1 and Secreted Human Intestinal Carboxylesterase, in Combination with Cyclophosphamide and Irinotecan

Abstract

The treatment of malignant glioma is currently ineffective. Oncolytic viruses are being explored as a means to selectively lyse tumor cells in the brain. We have engineered a mutant herpes simplex virus type 1 with deletions in the viral UL39 and g 1 34.5 genes and an insertion of the two prodrug activating genes, CYP2B1 and secreted human intestinal carboxylesterase. Each of these can convert the inactive prodrugs, cyclophosphamide and irinotecan (CPT-11), into their active metabolites, respectively. This new oncolytic virus (MGH2) displays increased antitumor efficacy against human glioma cells both in vitro and in vivo when combined with cyclophosphamide and CPT-11. Importantly, cyclophosphamide, CPT-11, or the combination of cyclophosphamide and CPT-11 does not significantly affect oncolytic virus replication. Therefore, MGH2 provides effective multimodal therapy for gliomas in preclinical models when combined with these chemotherapy agents. (Cancer Res 2005; 65(15): 6850-7)

Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling

“…Certainly, a number of previous studies with different viruses have reported increased viral replication linked to enhanced lytic cytotoxicity following combination treatment with either radiation or cytotoxic chemotherapy (30)(31)(32). However, others have reported no change or a reduction in viral replication in combination regimens with radiation or chemotherapy (23,(33)(34)(35)(36)(37). Our data clearly demonstrate by both viral plaque assay and quantitative PCR that the enhanced cytotoxicity of the combined treatment in V600D/E BRAF mutant cells was not due to increased viral replication.…”

Development of a rapid method to generate multiple oncolytic HSV vectors and their in vivo evaluation using syngeneic mouse tumor models

“…In fact, we have recently reported two papers in which the HSVQuik system was successfully utilized to generate novel oncolytic HSV vectors. 22,23 In vivo bioluminescent imaging has become a powerful means to evaluate and monitor tumor growth/clearance in response to various anticancer therapeutics in small animal models. [24][25][26] This new methodology is particularly useful when tumors are located deep inside the body such as in brain tumor, lung cancer and liver cancer models, where the assessment of tumor load is difficult without killing the animals.…”

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

“…This intrinsic diffusibility of 4-OH-CPA underlies the bystander cytotoxic response that is obtained when CPA is combined with P450-prodrug gene therapy. 13 The efficacy of P450 gene therapy can be enhanced in several ways, including combination with bioreductive prodrugs that are activated by P450 and/or P450 reductase, 14,15 by using a metronomic, antiangiogenic CPA treatment schedule, 16,17 and by using tumor cellreplicating herpes virus 18 and adenovirus 19 to spread the therapeutic P450 gene and augment tumor cell lysis.…”