Invited Speaker

Antiangiogenic Effect of Plasmid DNA Encoding Human Interleukin-12 in Metastatic Melanoma Patients and Combination Therapy
K. Moelling, J. Pavlovic, L. Elzaouk and L. Heinzerling et al.
Switzerland

Plasmid DNA encoding human Interleukin-12 (IL-12) was produced under GMP conditions and injected into lesions of nine patients with malignant melanoma (stage IV) previously treated with both, standard and non-standard therapies. The treatment was based on efficacy in preclinical studies with melanoma in mice and gray horses(1) and approved by Swiss authorities. The DNA was applied in cycles, three injections per cycle, up to seven cycles. Three therapy arms comprised low (2 mg), medium (4 mg) and high (10 to 20 mg) amounts of total DNA. The therapy was well tolerated. Three out of nine patients experienced a clinical response, 2 SD and 1 CR. One patient receiving a low dose of DNA experienced a long-lasting stabilization of the disease for more than three years, while the other two responders received high doses of DNA. All patients but one (P9) experienced a transient response at the intratumoral injection site. Immunohistochemical staining of responders showed local reduction of angiogenesis and lymphocyte infiltrations. All patients, in particular the responders (P3, P7, and P8) exhibited an antigen-specific immune response against MAGE-1 and MART-1. Biopsies of responders showed some increase of IL-12, IP-10 and IFN-γ (2). Compassionate trials with neurofibromatosis and cancer have been inititated. Therapy-related expression profiling is under way. Combinations of IL-12 DNA with other therapies show significant increase of efficacy in preclinical studies (3,4).

(1)Heinzerling, L., Feige, K., Rieder, S., Akens, M., Dummer, R., Stranzinger, G., Moelling, K. (2001). Tumor regression induced by intratumoral injection of DNA coding for human interleukin 12 into melanoma metastases in gray horses. J. Mol. Med. 78, 692-702.

(2)Heinzerling, L., Burg, G., Dummer, R., Oberholzer, P., Schultz, J., Elzaouk, L., Pavlovic. J., Moelling. K. Intratumoral injection of DNA encoding human interleukin-12 into patients with metastatic melanoma (2005): Clinical Efficacy Hum Gene Therapy 16:35- 48.

(3) Elzaouk, L., Pavlovic, J., Moelling, K. (2006). Analysis of antitumor activity elicited by vaccination with combinations of IL-12 DNA with gp100 DNA or the chemokine CCL21 in vivo. Hum Gene Ther 17, 859-870.

(4) Elzaouk, L., Pavlovic, J., Moelling, K. (2006). Analysis of antitumor activity elicited by vaccination with combinations of IL-12 DNA with gp100 DNA or the chemokine CCL21 in vivo. Hum Gene Ther 17, 859-870.