Intratumoral Injection of INGN 241, a Nonreplicating Adenovector Expressing the Melanoma-Differentiation Associated Gene-7 (mda-7/IL24): Biologic Outcome in Advanced Cancer Patients

Abstract

The mda-7 gene (approved gene symbol IL24) is a novel tumor suppressor gene with tumor-apoptotic and immune-activating properties. We completed a Phase I dose-escalation clinical trial, in which a nonreplicating adenoviral construct expressing the mda-7 transgene (INGN 241; Ad-mda7) was administered intratumorally to 22 patients with advanced cancer. Excised tumors were evaluated for vector-specific DNA and RNA, transgenic MDA-7 expression, and biological effects. Successful gene transfer as assessed by DNA- and RT-PCR was demonstrated in 100% of patients evaluated. DNA analyses demonstrated a dose-dependent penetration of INGN 241 (up to 4 x 10(8) copies/mug DNA at the 2 x 10(12) vp dose). A parallel distribution of vector DNA, vector RNA, MDA-7 protein expression, and apoptosis induction was observed in all tumors, with signals decreasing with distance away from the injection site. Additional evidence for bioactivity of INGN 241 was illustrated via regulation of the MDA-7 target genes beta-catenin, iNOS, and CD31. Transient increases (up to 20-fold) of serum IL-6, IL-10, and TNF-alpha were observed. Significantly higher elevations of IL-6 and TNF-alpha were observed in patients who responded clinically to INGN 241. Patients also showed marked increases of CD3+CD8+ T cells posttreatment, suggesting that INGN 241 increased systemic TH1 cytokine production and mobilized CD8+ T cells. Intratumoral delivery of INGN 241 induced apoptosis in a large volume of tumor and elicited tumor-regulatory and immune-activating events that are consistent with the preclinical features of MDA-7/IL-24.

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

“…Forced expression of E-cadherin in cultured cells, and transgenic mouse models of carcinogenesis, results in impaired metastatic and invasive phenotypes. 33,34 Here, we show that Herceptin, alone and in combination with Ad-mda7, is able to upregulate specifically E-cadherin in Her-2 þ cells, and to sequester its binding partner b-catenin to the plasma membrane (Figure 5a and b, left panel), thereby inhibiting its nuclear translocation and inhibiting b-catenin-induced transcriptional activation of cell migration and cell proliferation signals.…”

“…Differences in tumor size were analyzed for significance by the Student's t-test. Enhanced in vitro growth inhibitory and cytotoxic activity of Ad-mda7 and Herceptin in Her-2 þ breast cancer cells The antiproliferative effects of Ad-mda7 in various cancer cell types have been demonstrated in previous studies; [16][17][18][19][20][21][22][24][25][26][27][28][29][30][31][32][33][34]36 and the relevance of these findings to the clinical setting is supported by in vivo lung and breast xenograft models. 17,21 To corroborate that the Her-2 receptors expressed by the breast cancer cells are functional, we evaluated cell death in MDA-MB-453 and MCF-7 lines treated with increasing amounts of Herceptin (0-100 mg/ ml).…”

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.…”

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

“…The results obtained from this trial demonstrate both safety and clinical efficacy. 22 In addition to its direct apoptosis-inducing properties, Ad.mda-7 also shows antiangiogenic, immunostimulatory and potent 'bystander' antitumor activities. 23,24 These exciting results provide direct support for using mda-7/ IL-24 in developing an effective gene-based therapy for cancer.…”