Clinical and local biological effects of an intratumoral injection of mda-7 (IL24; INGN 241) in patients with advanced carcinoma: a phase I study

Abstract

The melanoma differentiation-associated gene-7 (mda-7; approved gene symbol IL24) is a tumor suppressor gene whose expression induces selective apoptosis in tumor cells. To characterize the safety and biologic activity of mda-7 gene transfer, we conducted a phase I trial using intratumoral injections of an adenovirus containing the mda-7 construct (Ad-mda7; INGN 241; 2 x 10(10) to 2 x 10(12) vp) in 28 patients with resectable solid tumors. One hundred percent of injected lesions demonstrated INGN 241 vector transduction, transgenic mRNA, elevated MDA-7 protein, and apoptosis induction, with the highest levels near the injection site. Apoptosis of cells in injected tumors was consistently observed even in heavily pretreated patients. INGN 241 vector DNA and mRNA were detected more than 1 cm from the injection site, whereas MDA-7 protein and bioactivity were more widely distributed. Toxicity attributable to the injections was self-limiting and generally mild; however, one patient experienced a grade 3 SAE possibly related to the study drug. Evidence of clinical activity was found in 44% of lesions with the repeat injection schedule, including complete and partial responses in two melanoma patients. Thus intratumoral administration of INGN 241 is well tolerated, induces apoptosis in a large percentage of tumor cells, and demonstrates evidence of clinically significant activity.

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

“…A phase I trial using intratumoral injections of Ad-IL-24 (INGN 241) was conducted in patients with refractory cancer. [14][15][16] As expected, INGN 241 can induce apoptosis in a large percentage of tumor volume via a single intratumoral injection. However, as the INGN 241 virus is nonreplicating, the clinically significant response can be seen only with repeat injection of INGN 241.…”

A cancer terminator virus eradicates both primary and distant human melanomas

“…mda-7 (INGN 241) was very encouraging, indicating that multiple intratumoral injections could elicit an objective clinical response with complete tumor regression in one melanoma patient. 13,16,18,[27][28][29] Of added significance, all of the patients in the clinical trial had already received several rounds of prior therapy (chemotherapy and/or radiation therapy) and the efficacy of Ad.mda-7 in these patients strongly suggests that administration of Ad.mda-7 in patients with early stage cancer might provoke an even more pronounced therapeutic response. These findings firmly establish mda-7/IL-24 as a bona fide candidate suppressor gene with potential to provide an effective alternative to conventional cancer treatment modalities.…”

“…[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.…”

Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) improves therapeutic efficacy in low CAR prostate cancer cells

“…[12][13][14][15][16][17] Forced expression of mda-7/IL-24, using Ad.5 (Ad.5-mda-7), inhibits growth and kills a broad spectrum of established cancer cell lines in vitro, without exerting injurious effects in multiple types of normal human epithelial cells, fibroblasts, melanocytes or astrocytes. [16][17][18][19][20][21] Considering its robust cancer-specific apoptosis-inducing ability (by inducing endoplasmic reticulum stress) and tumor growth-suppressing properties in nude mice human tumor xenograft models, Ad.mda-7 (INGN 241) was evaluated in a phase I clinical trial in patients with advanced cancers. The results obtained from this trial demonstrate both safety and clinical efficacy.…”