mda-7/IL-24, A Novel Cancer Selective Apoptosis Inducing Cytokine Gene: From the Laboratory into the Clinic

Abstract

An obstacle to effective gene-based cancer therapies is the limited number of cancer-specific growth suppressing and apoptosis-inducing genes. Using a differentiation induction subtraction hybridization (DISH) approach with human melanoma cells, melanoma differentiation associated (mda) genes were isolated that display elevated expression as a function of irreversible growth arrest, cancer reversion and terminal differentiation. This screening paradigm resulted in the cloning of mda-7 in the context of terminal differentiation of human melanoma cells. Based on its structure, chromosomal location, sequence homology and cytokine-like properties, mda-7 has now been renamed IL-24 and classified as a member of the expanding IL-10 cytokine gene family. Expression of mda-7/IL-24 inversely correlates with melanoma progression and administration of mda-7/IL-24 by means of a replication incompetent adenovirus, Ad.mda-7, results in growth suppression and apoptosis in melanoma cells as well as in a broad-spectrum of additional cancer cell types. In contrast, Ad.mda-7 does not elicit deleterious effects in normal cells, including those of epithelial, fibroblast, astrocyte, melanocyte or endothelial origin. Based on these distinctive properties and anti-tumor and anti-angiogenic activities in human tumor xenograft animal models, mda-7/IL-24 has now entered the clinical arena. A Phase I/II clinical trial in patients with advanced carcinomas involving intratumoral administration of mda-7/IL-24 [using a replication incompetent adenovirus; ING241 (Ad.mda-7)] has documented that this gene is safe and well tolerated by patients and a single virus injection elicits apoptosis in a majority of the tumor. Current data suggests that mda-7/IL-24 may function as a dual-acting cytokine in which its normal physiological functions may be related to specific aspects of the immune system and over-expression culminates in cancer-specific apoptosis. This review will provide a prospectus of our current understanding of mda-7/IL-24.

The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer

“…Furthermore, the special point was that no cytotoxicity mediated by IL-24 in a variety of normal tissue cells was found. 32,33 In addition to the feature of selective apoptosis induction, additional antitumor properties of mda-7/IL-24 were also observed. These include inhibition of tumor cell invasion and migration, 34,35 potent antiangiogenic effects, 36,37 immune stimulatory activity 38,39 and direct bystander cytotoxicity.…”

A cancer terminator virus eradicates both primary and distant human melanomas

“…[17][18][19][20][21][22][23][24][25][26] A momentous step in the evolution of mda-7/IL-24 as a potential therapeutic gene was the evaluation of Ad.mda-7 (INGN 241) in a phase-I clinical trial by intratumoral injection in patients with advanced solid tumors, including melanomas. 13,16,18,[27][28][29] These studies indicated that mda-7/IL-24 was safe and could induce as much as 70% apoptosis in tumors following a single injection of recombinant virus, and with multiple injections, it promoted objective clinical responses, especially in melanoma patients. 13,16,18,[27][28][29] This exciting transition from the 'laboratory to the clinic' provides direct support for using mda-7/IL-24 to develop an effective gene-based therapy for cancer, including metastatic melanoma.…”

“…13,16,18,[27][28][29] These studies indicated that mda-7/IL-24 was safe and could induce as much as 70% apoptosis in tumors following a single injection of recombinant virus, and with multiple injections, it promoted objective clinical responses, especially in melanoma patients. 13,16,18,[27][28][29] This exciting transition from the 'laboratory to the clinic' provides direct support for using mda-7/IL-24 to develop an effective gene-based therapy for cancer, including metastatic melanoma.…”

Clinical development directions in oncolytic viral therapy

“…Physical shielding to enhance delivery and reduce viral clearance is being tested [170][171][172][173][174][175] (plus Rehman 2001). Currently, liposome encapsulated, polymer coated, and cell carrier modes of oncolytic virus delivery are being developed for preclinical testing.…”

“…The liposome and polymer coated methods can be coated with tumorspecific antibodies, peptides or small molecules to further enhance tumor-specific uptake and delivery. [176][177][178][179][180][181][182][183][184] Plasmapheresis rotation of viral serotype [170][171][172][173][174][175] and B-cell suppression have had limited testing as methods to reduce normal immune reactivity against administered viral particles. Restoration of the E3 region of the viral genome or E3 protein activity, in an effort to limit effects of tumor necrosis factor-a through combination with soluble tumor necrosis factor-a receptors, demonstrates positive effect.…”