Intratumoral Injection of DNA Encoding Human Interleukin 12 into Patients with Metastatic Melanoma: Clinical Efficacy

Abstract

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 nonstandard therapies. The treatment was based on efficacy in preclinical studies with melanoma in mice and gray horses. The DNA was applied in cycles, three injections per cycle, for 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 of nine patients experienced a clinical response: two stable disease and one complete remission. One patient receiving a low dose of DNA experienced a long-lasting stabilization of the disease for more than 3 years, whereas the other two responders received high doses of DNA. All patients but one (patient 9) experienced a transient response at the intratumoral injection site. Immunohistochemical staining of responder sections showed local reduction of angiogenesis and lymphocyte infiltrations. All patients, in particular the clinical and local responders (patients 3, 7, and 8), exhibited an antigen-specific immune response against MAGE-1 and MART-1, which in some cases preexisted. Biopsies of responders showed some increase in IL-12, IP-10, and IFN-(). Serum levels revealed fluctuations. The results show that intratumoral injection of DNA produced some beneficial clinical effect. DNA encoding a cytokine may be useful as a therapeutic or adjuvant against various human cancers.

New insights into IL-12-mediated tumor suppression

“…delivery of a plasmid encoding IL-12 led to some beneficial clinical effect at the tumor site and even in non-treated lesions. [127][128][129] The treatment seemed however less efficient when IL-12 was delivered encoded by a vector derived from a highly attenuated strain of the canarypox virus. 130 Viral delivery of IL-12 was also used in patients with advanced digestive cancer, but only led to mild antitumor effects.…”

Transposon-based interferon gamma gene transfer overcomes limitations of episomal plasmid for immunogene therapy of glioblastoma

“…Similarly, repeated administration of an IL-12-encoding plasmid into melanoma patients demonstrated antitumor activity in select patients. 6 However, the concentration of IL-12 in serum was not higher than pretreatment levels for more than 1-2 days after each plasmid administration, again highlighting the transient effects of plasmid vectors. 6 Recently, several recombinase systems have been developed that allow chromsomal integration and long-term expression following a single administration of plasmid DNA, including transposable elements and bacteriophage integrases (see Groth and Calos, 27 and Ivics and Izsvak 28 for review).…”

“…In contrast to nonviral vectors, viral vectors have often facilitated sustained expression of antitumor proteins from a single administration in murine models. [3][4][5] A typical approach to overcoming the transient expression of nonviral gene transfer has been repeated administration, which has produced encouraging results in patients with metastatic melanoma 6 and renal cell carcinoma. 7 New approaches that allow sustained gene expression could potentially reduce the number of administrations required, and increase the efficacy of nonviral cancer gene therapy vectors.…”

Interleukin-12 and photocarcinogenesis

“…The therapy was well tolerated. Three of nine patients experienced a clinical response: two stable disease and one complete remission (Heinzerling et al, 2005). All patients but one experienced a transient response at the intratumoral injection site.…”