Novel radioimmunotherapy for lymphoma and solid tumours both as a single agent and in combination with the vascular disrupting agents

摘要

Background: Single-agent radioimmunotherapy (RIT) has demonstrated efficacy in B-celludlymphomas but has been relatively disappointing in solid tumours. To improveudits efficacy combinations of RIT with new agents are being investigated. Oneudrational combination, from preclinical studies, is RIT and a vascular disruptingudagent (VDA).udAim: To complete two Phase I clinical studies: 1) using single-agent RIT in Hodgkinudlymphoma (HL) and T-cell Lymphomas and 2) combining RIT withudCombretastatin-A4-Phosphate (CA4P) for solid tumours. Angiogenic cytokinesudand circulating cells were investigated as potential biomarkers for VDA inducedudhypoxia.udMethods: Two phase I, open-label, non-randomised dose-escalation clinical trials wereudcompleted. In the lymphomas a murine CD25-antibody conjugated to 131I wasudused in 14 patients. In CEA-expressing gastrointestinal tumours an anti-CEAud(carcino-embryonic antigen) antibody, A5B7 was used with CA4P in 12 patients.udELISA (enzyme-linked immunosorbent assay) measured angiogenic cytokines inudserum and flow cytometry assessed Tie-2 monocytes and EPC’s. Hepatic arteryudembolisation was used as a model for acute tumour hypoxia.udResults: The 131I-CHT25 study demonstrated efficacy with a response rate of 67% at orudabove the MTD (maximum tolerated dose). In solid tumours 131I-A5B7 and CA4Pudproduced one minor response with a corresponding tumour marker fall.udErythropoietin, VEGF (vascular endothelial growth factor) and Tie-2 monocytesudincreased post embolisation and would merit further investigation as potential biomarkers. Angiopoietin 2 appeared elevated in both malignancy and liveruddisease and was an independent prognostic factor but did not rise postembolisation.udThis supported previous work suggesting angiopoietin-2 wasudderived from surrounding liver rather than tumour.udConclusion: Single agent RIT appears effective in lymphoma but further research is requiredudin solid tumours. More potent VDAs have since entered clinical trials but theuddevelopment of biomarkers to determine response will be vital. VEGF,uderythropoietin, Tie-2 monocytes and EPC’s would merit further investigation forudthat role.