JPP 2008, 60: 987–998 © 2008 The Authors Received January 31, 2008 Accepted May 6, 2008 DOI 10.1211/jpp.60.8.0006 ISSN 0022-3573 987 New insights into the mechanisms of action of radioimmunotherapy in lymphoma Andrei Ivanov, Ruth Swann and Tim Illidge Abstract The exquisite sensitivity of haematological malignancies to targeted radiation alongside the impres- sive results achieved by the pioneers in this field suggests that radioimmunotherapy is likely to be a productive area for future clinical research. Recent experimental work has demonstrated that the combination of targeted radiation and antibody effector mechanisms are critical to long-term clear- ance of tumour. This review provides the background of clinical and biological insights into the mechanisms of action of radioimmunotherapy. Introduction—The principles of radioimmunotherapy The use of monoclonal antibodies (mAbs) in routine clinical practice is now well estab- lished and has led to impressive improvements in outcome for patients with a range of human cancers (Robak 2004; Adams & Weiner 2005). Although the single-agent activity of most mAbs has been modest, when used in combination with both chemotherapy and radio- therapy highly impressive increases in clinical responses and improvement in survival have been seen (Coiffier et al 2002, 2003; Robak 2004). Radioimmunotherapy (RIT) is, in contrast, the administration of mAb or mAb-derived constructs, which are chemically conjugated to therapeutic radioisotopes targeted to tumour. In this context, mAbs were initially regarded simply as direct carriers for the radioisotope, which deliver systemically targeted cytotoxic radiation to areas of disease, with relative sparing of normal tissue. It is, however, becoming clearer that the mAb effector mechanisms may also play an important additional role in killing lymphoma cells. The nature of RIT determines that its efficacy depends on a number of factors, including the properties of the targeted antigen (specificity, density, availability, shedding and heterogeneity of expression), the tumour (degree of vascularization, blood flow and permeability), the mAb (specificity, immunoreactivity, stability and affinity) and the properties of the chosen radioisotope (emission characteristics, half-life and bioavailability) (Knox & Meredith 2000). A wide variety of different mAbs, delivery schedules, radioisotopes and doses of radio- activity have been used in RIT and have resulted in impressive durable partial and complete responses in the treatment of non-Hodgkin’s lymphoma (NHL) (Park & Press 2007). In this review the principles of radioimmunotherapy will be discussed along with some recent data that provide new insights into the mechanism of action of RIT. Finally, the clinical data that led to the two radioimmunconjugates, 131 I-tositumomab and 90 Y-ibritumomab, being approved by the US FDA (US Food and Drug Administration) and 90 Y-ibritumomab tiuxetan within the EU, will be discussed. Antigen targeting The use of radiotherapy in the treatment of haematological malignancies is well established and for localized disease it is a highly effective treatment modality, given the exquisite sensitivity of lymphomas and leukaemias to radiation-induced cell death. The systemic nature of the majority of lymphomas and leukaemias, however, makes localized irradiation inappropriate for most patients. Therefore the systemic delivery of targeted radiation in the form of RIT is a logical strategy given for disseminated tumours, especially those known to be so radiosensitive. The effective delivery of RIT requires the selection of a suitable tumour antigen target. School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK Andrei Ivanov, Ruth Swann, Tim Illidge Correspondence: T. Illidge, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK. E-mail: tmi@manchester.ac.uk