ØYSTEIN FODSTAD:  FRIDAY 31 MARCH 2006, 16:20

Basic and Translational Research on Immunotoxins and Immunotoxin/Drug Combinations

Øystein Fodstad¹, Olav Engebraaten², Karianne Risberg², Yvonne Andersson^2
1Cancer Research Institute, University of South Alabama, and Institute for Cancer Research, Norwegian, 36688-0002 Mobile, USA; ²Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, N-0310 Oslo, Norway

Several problems faced with the use of chemically conjugated immunotoxins (ITs) were expected to be solved by using toxin fragments, humanized antibodies and/or recombinant molecules. However, the clinical experience has been disappointing, possibly because of limitations related to pharmacodynamics and internalization. We have worked with Pseudomonas exotoxin A containing conventional ITs, two of which showed promising preclinical effects. These were GMP produced and toxicity tested in primates and one is in a clinical phase trial. It has safely been administered to the patients but a dose-limiting toxicity level has not yet been reached. In parallel, we have investigated the mechanisms of action of several ITs and shown that they initially induce a mitochondrial-dependent survival response before killing the cells by inducing apoptosis and protein synthesis inhibition. Attempts were made to find agents that could act synergistically with the ITs aiming at obtaining increased anti-tumor effects with a reduced IT dose. With two anti-carcinoma ITs we found strong synergistic effects in vitro and in vivo with a drug in clinic use for non-cancer conditions. Moreover, in preliminary in vitro experiments promising effects of a combination of an anti-melanoma IT and small molecule inhibitors have been seen. In summary, a clinical trial with a conventional IT is ongoing with no unexpected side effects. Furthermore, in preclinical experiments synergistic effects have been found with combinations of different ITs and selected compounds, supporting development towards clinical use.

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