Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients.
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.
Tong
Alex W
AW
Baylor Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA.
Nemunaitis
John
J
Su
Dan
D
Zhang
Yuan
Y
Cunningham
Casey
C
Senzer
Neil
N
Netto
George
G
Rich
Dawn
D
Mhashilkar
Abner
A
Parker
Karen
K
Coffee
Keith
K
Ramesh
Rajagopal
R
Ekmekcioglu
Suhendan
S
Grimm
Elizabeth A
EA
van Wart Hood
Jill
J
Merritt
James
J
Chada
Sunil
S
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000493:pharmacokinetics; D006801:Humans; D007110:Immunity, Active / Q000276:immunology; D007267:Injections; D007378:Interleukins / Q000235:genetics* / Q000627:therapeutic use*; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009367:Neoplasm Staging; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015534:Trans-Activators / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D016896:Treatment Outcome; D014779:Virus Replication; D051176:beta Catenin; D000099180:Interleukin-24
D015415:Biomarkers; D003598:Cytoskeletal Proteins; D007378:Interleukins; D015534:Trans-Activators; D051176:beta Catenin; D000099180:Interleukin-24; C495270:CTNNB1 protein, human