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Review
. 2018 Aug;233(8):5684-5695.
doi: 10.1002/jcp.26421. Epub 2018 Feb 27.

Cancer Terminator Viruses (CTV): A Better Solution for Viral-Based Therapy of Cancer

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Free PMC article
Review

Cancer Terminator Viruses (CTV): A Better Solution for Viral-Based Therapy of Cancer

Luni Emdad et al. J Cell Physiol. .
Free PMC article

Abstract

In principle, viral gene therapy holds significant potential for the therapy of solid cancers. However, this promise has not been fully realized and systemic administration of viruses has not proven as successful as envisioned in the clinical arena. Our research is focused on developing the next generation of efficacious viruses to specifically treat both primary cancers and a major cause of cancer lethality, metastatic tumors (that have spread from a primary site of origin to other areas in the body and are responsible for an estimated 90% of cancer deaths). We have generated a chimeric tropism-modified type 5 and 3 adenovirus that selectively replicates in cancer cells and simultaneously produces a secreted anti-cancer toxic cytokine, melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24), referred to as a Cancer Terminator Virus (CTV) (Ad.5/3-CTV). In preclinical animal models, injection into a primary tumor causes selective cell death and therapeutic activity is also observed in non-injected distant tumors, that is, "bystander anti-tumor activity." To enhance the impact and therapeutic utility of the CTV, we have pioneered an elegant approach in which viruses are encapsulated in microbubbles allowing "stealth delivery" to tumor cells that when treated with focused ultrasound causes viral release killing tumor cells through viral replication, and producing and secreting MDA-7/IL-24, which stimulates the immune system to attack distant cancers, inhibits tumor angiogenesis and directly promotes apoptosis in distant cancer cells. This strategy is called UTMD (ultrasound-targeted microbubble-destruction). This novel CTV and UTMD approach hold significant promise for the effective therapy of primary and disseminated tumors.

Keywords: CTV; cancer; mda-7/IL-24; viral therapy.

Conflict of interest statement

Conflict of Interest

PBF is a co-founder and owns stock in Cancer Targeting Systems (CTS). Virginia Commonwealth University, Johns Hopkins University and Columbia University own stock in CTS.

Figures

Figure 1
Figure 1
PEG-prom drives expression of GFP selectively in cancer cells, but not in normal cells. Upper panel, Schematic representation of utility of PEG promoter to deliver reporter genes (green fluorescence protein (GFP) or luciferase (luc)) using replication incompetent Ads. Lower panel, PEG-Prom drives the expression of GFP only in cancer cells but not in normal cells. A. Normal primary human prostate epithelial cells (HuPEC) and human prostate carcinoma cells (Du-145, PC-3 and LNCaP); B. Immortal normal prostate epithelial cells (P69) and progressed tumorigenic P69-derived cells (M2182) and progressed P69-derived metastatic cells (M12); C. Normal primary human breast epithelial cells (HMEC) and human breast carcinoma cells (MCF7, T47D, MDA-MB-157, MDA-MB-231 and MDA-MB-453). The indicated cells were infected with either Ad.CMV-GFP or Ad.PEG-GFP at a moi of 100 pfu per cell, and GFP expression was analyzed by an immunofluorescence microscope at 2 day postinfection. (Adapted from Su et al, PNAS; 2005)
Figure 2
Figure 2
Constructing a tropism-modified adenovirus (Ad.5/3) carrying the mda-7/IL-24 gene. The genome of Ad.5/3.mda-7 was generated by homologous recombination between the linearized plasmid pShCMV.mda-7 and 8st81-digested genomic DNA of Ad.5/3-Luc, and kanamycin selection resulted in the pAd.5/3-mda-7 genome, where the CMV promoter in place of the early viral El region drives mda-7/IL-24 expression. This plasmid was digested with Pad to release viral ITRs and transfected in A549 cells to rescue the Ad.5/3-mda-7. (Das et al., Adv. Cancer Res., 2012)
Figure 3
Figure 3
Delivery of Cancer Terminator Viruses (CTVs) systemically following complexing with microbubbles (MB) coupled with ultrasound-targeted MB destruction, the UTMD approach. Complexes of CTVs with MBs are delivered intravenously (Box A, Ad incorporated in the lipid shell of MBs), which are released at the primary tumor site by the application of ultrasound (Box B, sonoporation of MBs in the tumor with an ultrasound probe). After intracellular entry, the CTVs replicate selectively in tumor cells, resulting in robust production of mda-7/IL-24 that when translated into MDA-7/IL-24 protein cause ER stress and “unfolded protein stress response” and cancer cell death. MDA-7/IL-24 is subsequently released into the circulatory system and due to virtue of its “bystander activity” (Box C, binding of MDA-7/IL-24 with IL-20R1/IL-20R2 or IL-20R1/IL-22R1 and promoting intracellular signaling leading to autocrine production of MDA-7/IL-24), which would be anticipated to induce tumor-specific apoptosis of primary and distant tumors, antiangiogenic effects in primary and distant tumor vasculatures, and immune modulatory effects targeting tumors for immune destruction. It is believed to be the “summation” of these multifaceted antitumor properties of MDA-7/IL-24 that promotes selective destruction of both primary and distant tumors. (Adapted from Das et al., Adv. Cancer Res., 2012).

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