Potent antitumor effects of combined therapy with a telomerase-specific, replication-competent adenovirus (OBP-301) and IL-2 in a mouse model of renal cell carcinoma

Abstract

OBP-301 (a telomerase-specific, replication-competent adenovirus with hTERT promoter) was constructed in a previous study and it showed a strong anticancer effect by inducing cell lysis in human lung and prostate cancer cells. This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell-killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells. In in vivo experiment, luciferase-expressing RENCA cells were implanted in the left kidney and lung of BALB/c mice to prepare the RCC metastatic model. The animals were randomly divided into four treatment groups: PBS, IL-2 alone, OBP-301 alone and the combination. The analyses of orthotopic tumor weight, lung metastasis and luciferin-stained tumor images 14 days after each treatment showed significant tumor growth inhibition in the combination group in comparison with that in the OBP-301-or IL-2-treated groups. In addition, the percentage of regulatory T-cells (Tregs) in the combination group was significantly suppressed in comparison with that in the PBS and single-agent treatment groups. The outcomes of this study suggest that tumor-specific oncolytic immunovirotherapy may become an attractive strategy for the treatment of human RCC.

Molecular imaging and pharmacokinetics of 99mTc‐hTERT antisense oligonucleotide as a potential tumor imaging probe

“…Therefore, targeting the catalytic subunit hTERT represents a promising approach for diminishing telomerase function that will probably not cause substantial side effects on telomerase‐negative somatic cells . Development of hTERT‐based probes has broad implications in oncology studies, such as clinical diagnosis, staging, therapy, monitoring therapeutic responses, and in biomedical research …”

Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging

“…The human telomerase reverse transcriptase (hTERT) promoter has been well characterized and determined to be available for cancer tissue-specific gene expression in a broad range of malignant tissue types (1)(2)(3). In previous studies, we have demonstrated that treatment with an hTERT-driven replication competent adenovirus, OBP-301, led to significant tumor regression in mouse models of prostate and renal cancer (4,5). However, the in vivo use of tissuespecific promoters, including hTERT, is often limited because the specific promoters can not lead to sufficient levels of therapeutic or reporter gene expression.…”

A novel targeting modality for renal cell carcinoma: human osteocalcin promoter‐mediated gene therapy synergistically induced by vitamin C and vitamin D3

“…Transcriptional regulation of transgene expression using tumor‐ or tissue‐specific promoters within adenoviral vectors has already been attempted to treat tumors 7, 8. However, only a limited number of promoters that restrict gene expression to RCC have been studied 9–11 because clinically defined RCC tumor markers whose promoter is highly active in tumors but either silent or active at very low background levels in normal kidney cells are not available. Therefore, the development of a novel inducible promoter system that allows reliable and controllable transactivation of ectopic gene expression in restricted tissue or cell types by administration of inducing agents is essential for the success of a RCC targeted gene therapy that does not induce serious kidney damage.…”