Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): Biologic outcome in advanced cancer patients

Alex W. Tong, John Nemunaitis, Dan Su, Yuan Zhang, Casey Cunningham, Neil Senzer, George Netto, Dawn Rich, Abner Mhashilkar, Karen Parker, Keith Coffee, Rajagopal Ramesh, Suhendan Ekmekcioglu, Elizabeth A. Grimm, Jill van Wart Hood, James Merritt, Sunil Chada

Research output: Contribution to journalArticle

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 × 108 copies/μg DNA at the 2 × 1012 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 β-catenin, iNOS, and CD31. Transient increases (up to 20-fold) of serum IL-6, IL-10, and TNF-α were observed. Significantly higher elevations of IL-6 and TNF-α 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 TH 1 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.

Original languageEnglish (US)
Pages (from-to)160-172
Number of pages13
JournalMolecular Therapy
Volume11
Issue number1
DOIs
StatePublished - Jan 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Tong, A. W., Nemunaitis, J., Su, D., Zhang, Y., Cunningham, C., Senzer, N., Netto, G., Rich, D., Mhashilkar, A., Parker, K., Coffee, K., Ramesh, R., Ekmekcioglu, S., Grimm, E. A., van Wart Hood, J., Merritt, J., & Chada, S. (2005). Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): Biologic outcome in advanced cancer patients. Molecular Therapy, 11(1), 160-172. https://doi.org/10.1016/j.ymthe.2004.09.021