Phase I Study of the Intratumoral Administration of Recombinant Canarypox Viruses Expressing B7.1 and Interleukin 12 in Patients with Metastatic Melanoma

Abstract

The objective of this study was to evaluate the safety and activity of the intratumoral administration of the immune costimulatory molecule, B7.1, encoded by a vector derived from the canarypox virus, ALVAC (ALVAC-B7.1), alone and with the intratumoral injection of ALVAC encoding the immune-stimulatory cytokine, interleukin 12 (ALVAC-IL-12). Fourteen patients with metastatic melanoma who had s.c. nodules received intratumoral injections on days 1, 4, 8, and 11. Nine patients were given escalating doses of up to 25 Â 10 8 plaque-forming units of ALVAC-B7.1. Five patients were given 25 Â 10 8 plaque-forming units of ALVAC-B7.1combined with ALVAC-IL-12 50% tissue culture infective dose of 2 Â 10 6 .Toxicity was mild to moderate and consisted ofinflammatory reactions at the injection site and fever, chills, myalgia, and fatigue. Higher levels of B7.1 mRNA were observed in ALVAC-B7.1^injected tumors compared with saline-injected control tumors. Higher levels of intratumoral vascular endothelial growth factor and IL-10, cytokines with immune suppressive activities, were also observed in ALVAC-B7.1^and ALVAC-IL-12^injected tumors compared with saline-injected controls. Serum levels of vascular endothelial growth factor increased at day 18 and returned to baseline at day 43. All patients developed antibody to ALVAC. Intratumoral IL-12 and IFN-g mRNA decreased. Changes in serum IL-12 and IFN-g levels were not observed. Tumor regressions were not observed. The intratumoral injections of ALVAC-B7.1and ALVAC-IL-12 were well tolerated at these dose levels and at this schedule and resulted in measurable biological response. This response included the production of factors that may suppress the antitumor immunologic activity of these vectors.

Short-Term Intratumoral Interleukin-12 Expressed from an Alphaviral Vector Is Sufficient to Induce an Efficient Antitumoral Response Against Spontaneous Hepatocellular Carcinomas

“…However, the modest antitumoral responses mediated by vectors tested in clinical trials questions the translation of preclinical results (Sangro et al, 2004;Triozzi et al, 2005;Mahvi et al, 2007;Daud et al, 2008). We think that direct comparisons between available vectors in clinically relevant tumor models may enhance the success of gene therapy vectors in the clinic.…”

Direct inhibition of human acute myeloid leukemia cell growth by IL-12

“…First, it was reported that patients treated with IL-12 administered s.c. showed less severe side effects as compared to i.v. treated patients [26]; next, novel forms of IL-12 non-viral delivery such as alum, liposome and polymer-based delivery have shown in pre-clinical models promising effects and significantly reduced systemic toxicity [27][28][29]. Taken together, a clinical trial in AML patients appears to be feasible.…”

Polysaccharide Purified fromGanoderma lucidumInduces Gene Expression Changes in Human Dendritic Cells and Promotes T Helper 1 Immune Response in BALB/c Mice

“…Transfer of cytokine genes is thereby a possible strategy for cancer treatment and is currently being investigated for its clinical feasibility (Chiyo et al, 2004;Triozzi et al, 2005).…”