SOLUBLE E-SELECTIN IN CANCER-PATIENTS AS A MARKER OF THE THERAPEUTIC EFFICACY OF CM101, A TUMOR-INHIBITING ANTI-NEOVASCULARIZATION AGENT, EVALUATED IN PHASE-I CLINICAL-TRIAL

A polysaccharide toxin, GBS toxin, is produced by group B Streptococcu s (GBS) isolates from neonates who died of ''early-onset disease''. GB S toxin, named CM101 in the clinic, was hypothesized, on the basis of our previous in vivo studies, to induce inflammation in pulmonary neov asculature in neonates by cross-linking of embryonic receptors still e xpressed after birth and in tumor neovasculature in adults. Immunohist ochemical in vitro analysis of human biopsies showed that tumor neovas culature is indeed a binding site for CM101. In vivo studies in mice h ave demonstrated that CM101 induced inflammatory responses in neoplast ic tumor neovasculature causing inhibition of tumor growth and tumor c ell necrosis. These experimental observations warranted a phase I clin ical trial for CM101 as an anti-neovascularization agent in human canc er therapy. Cancer patients received one cycle of therapy consisting o f three treatments during 1 week. CM101 was administered over 15 min b y i.v. infusion. Dosages of 7.5 mu g/kg (1 U/kg), n = 3; 15 mu g/kg (2 U/kg), n = 6; 24.75 mu g/kg (3.3 U/kg), n = 3; and 37.5 mu g/kg (5 U/ kg), n = 3 were used. Enzyme-linked immunosorbent sandwich assays (ELI SA) of the patients' sera showed a marked elevation of soluble E-selec tin with a peak concentration observed at 8-12 h after each CM101 infu sion. The average baseline value for soluble E-selectin prior to the f irst treatment was 97.3 +/- 23.4 ng/ml (mean +/- SEM, n = 15) and the average peak level at 8 h was 441.6 +/- 62.4 (mean +/- SEM, n = 15; P < 0.001). Subsequent treatments gave average maximum soluble E-selecti n levels again at 8 h of 466.9 +/- 87.6 and 412.0 +/- 67.8 ng/ml, for treatments 2 and 3 respectively. Baseline values for treatments 2 and 3 were 192.3 +/- 26.4 and 226.4 +/- 26.1 ng/ml respectively (p < 0.01 versus treatment 1). Out of 15 patients, 5 showed tumor reduction or s tabilization and were given additional cycles of therapy. CM101 induce d an increase in soluble E-selectin levels, which remained elevated ov er baseline at the start of the following treatment cycles. The baseli ne remained elevated for several weeks after the final treatment, i.e. , P < 0.01 for levels before treatment 1 compared to those at week 4 a fter treatment. Elevated soluble E-selectin is considered proof of end othelial engagement in an inflammatory process. Our data support the c ontention that the inflammatory response observed in these cancer pati ents is targeting the tumor neovasculature and that measurement of sol uble E-selectin levels in patients treated with CM101 can provide impo rtant information on the magnitude of CM101-mediated neovascular endot helial activation and tumor cell damage in cancer of endothelial origi n, or cancer with a major neo-angiogenic component.