Dancey, G.S.; (2011) Novel radioimmunotherapy for lymphoma and solid tumours both as a single agent and in combination with the vascular disrupting agents. Doctoral thesis , UCL (University College London).

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Abstract

Background: Single-agent radioimmunotherapy (RIT) has demonstrated efficacy in B-cell lymphomas but has been relatively disappointing in solid tumours. To improve its efficacy combinations of RIT with new agents are being investigated. One rational combination, from preclinical studies, is RIT and a vascular disrupting agent (VDA). Aim: To complete two Phase I clinical studies: 1) using single-agent RIT in Hodgkin lymphoma (HL) and T-cell Lymphomas and 2) combining RIT with Combretastatin-A4-Phosphate (CA4P) for solid tumours. Angiogenic cytokines and circulating cells were investigated as potential biomarkers for VDA induced hypoxia. Methods: Two phase I, open-label, non-randomised dose-escalation clinical trials were completed. In the lymphomas a murine CD25-antibody conjugated to 131I was used in 14 patients. In CEA-expressing gastrointestinal tumours an anti-CEA (carcino-embryonic antigen) antibody, A5B7 was used with CA4P in 12 patients. ELISA (enzyme-linked immunosorbent assay) measured angiogenic cytokines in serum and flow cytometry assessed Tie-2 monocytes and EPC’s. Hepatic artery embolisation was used as a model for acute tumour hypoxia. Results: The 131I-CHT25 study demonstrated efficacy with a response rate of 67% at or above the MTD (maximum tolerated dose). In solid tumours 131I-A5B7 and CA4P produced one minor response with a corresponding tumour marker fall. Erythropoietin, VEGF (vascular endothelial growth factor) and Tie-2 monocytes increased post embolisation and would merit further investigation as potential biomarkers. Angiopoietin 2 appeared elevated in both malignancy and liver disease and was an independent prognostic factor but did not rise postembolisation. This supported previous work suggesting angiopoietin-2 was derived from surrounding liver rather than tumour. Conclusion: Single agent RIT appears effective in lymphoma but further research is required in solid tumours. More potent VDAs have since entered clinical trials but the development of biomarkers to determine response will be vital. VEGF, erythropoietin, Tie-2 monocytes and EPC’s would merit further investigation for that role.

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