Gene Electrotransfer of Plasmid Antiangiogenic Metargidin Peptide (AMEP) in Disseminated Melanoma: Safety and Efficacy Results of a Phase I First-in-Man Study

Abstract

Antiangiogenic metargidin peptide (AMEP) is a novel anticancer agent exerting antiproliferative and antiangiogenic effects by binding to αvβ3 and α5β1 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues. This first-in-man phase I study investigated safety and tolerability of intratumoral plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Five patients with disseminated melanoma without further treatment options were treated at two dose levels (1 and 2 mg DNA). In each patient, two cutaneous lesions were identified (one treated and one control). At day 1 and day 8, plasmid AMEP was injected intratumorally followed by electrotransfer. Patients were monitored weekly until day 29, and at day 64. Local efficacy was assessed at day 29 by direct measurement, and posttreatment biopsies for AMEP mRNA levels were evaluated by reverse transcriptase quantitative polymerase chain reaction. Plasmid copy number in blood and urine was determined by quantitative polymerase chain reaction. Minimal systemic toxicity was observed, including transient fever and transitory increase in C-reactive protein. No related serious adverse events occurred. Plasmid AMEP was detected in plasma but not in urine. AMEP mRNA was found in three of five treated lesions and none of the control lesions. At day 29, all five treated lesions were stable in diameter, whereas four of five control lesions increased more than 20%. No response occurred in distant lesions. This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma shows that the procedure and drug are safe and that local transfection was obtained.

Gene electrotransfer of plasmid AMEP, an integrin-targeted therapy, has antitumor and antiangiogenic action in murine B16 melanoma

“…The clinical study on five patients treated with Plasmid AMEP intratumoral gene electrotransfered demonstrated good tolerability of Plasmid AMEP, local antitumor effectiveness in the treated lesions and no related severe adverse events. 8 In our study, the antitumor effectiveness in vivo was very similar in both metastatic and non-metastatic melanoma models with no significant difference in tumor growth delay between the tumor models observed. However, tumor mRNA levels after GET of Plasmid AMEP were almost 10-fold higher in the highly metastatic B16F10 tumor model, indicating that AMEP mRNA expression levels did not correlate with the biological effect, suggesting that even a low level of AMEP expression is sufficient to delay tumor growth in the models.…”

“…Plasmid AMEP delivery was well tolerated with local antitumor effectiveness in treated lesions observed, whereas no related severe adverse effects were noted. 8 Phase I/II studies were then launched, which were aimed at delivering Plasmid AMEP intramuscularly, so as to exert a systemic therapy to multiple metastases (www.clinicaltrial.gov).…”

Antimetastatic Potential in Mice after Gene Therapy with Plasmid AMEP

“…Moreover, the first clinical Phase I/II study with intratumoraly administrated Plasmid AMEP conducted on 5 patients demonstrated good tolerability of Plasmid AMEP and local antitumor effectiveness in the treated lesions. No effect on distant lesions was observed [7].…”

“…Moreover, first gene therapy clinical study with intratumorally administrated Plasmid AMEP was conducted. The study showed local antitumor effectiveness in the treated lesions, with no related severe adverse events after gene therapy with Plasmid AMEP [7]. While intratumoral gene therapy clinical study was supported with pre-clinical research, another two phase I/II clinical studies, aimed at delivering Plasmid AMEP intramuscularly, were launched based on research with inducible plasmid coding for RDD (AMEP's equivalent).…”

Drug and Gene Electrotransfer in Cancer Therapy

“…1.2 Different objectives for gene electrotransfer to skin. Gene electrotransfer to skin has perspectives in "systemic treatment," "local treatment," and "DNA vaccinations" tumors (Daud et al 2008b;Spanggaard et al 2013), using genes coding for respectively a cytokine (interleukin-12) or an antiangiogenic, antiproliferative molecule (Spanggaard et al 2013). …”