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Targeted therapy

Led by Professor Tim Illidge

Development of radioimmunotherapy in cancer

Monoclonal antibodies (mAb) are increasingly being integrated into radiotherapy and chemotherapy treatment schedules leading to improved tumour responses and more recently to improved survival. Integrating mAb with irradiation appears a promising strategy, given the different mechanisms of action and non-overlapping toxicity profiles. mAb may be administered concurrently with irradiation or may be conjugated with radioisotopes as part of RIT. In clinical RIT a wide variety of different antibodies, delivery schedules, radioisotopes and doses of radioactivity have been used. Despite the heterogeneity of approach a common observation to all of these studies is that low-grade and transformed lymphomas are highly sensitive to RIT. These studies have culminated in the first RIT reagent ⁹⁰Y Ibritumomab (Zevalin^TM) gaining recent European MEA approval for the treatment of cancer and ¹³¹I labelled Tositumomab (Bexxar^TM) is approved as well in the US. Despite the considerable clinical successes with RIT, the mechanisms of action of RIT are poorly understood. This relative lack of knowledge makes it very difficult to know the best way to optimise and schedule RIT into treatment protocols of B cell lymphomas. The group's experimental work is therefore focused on demonstrating the relative the importance of mAb specificity and mAb effector mechanisms to improving therapeutic outcomes when combining mAb with irradiation.

Solid cancer treatment

When combined with chemotherapy or external beam irradiation, mAb are also producing highly promising data in the treatment of some solid cancers. Here mAb have the potential to trigger selective tumour cell death via cell surface signalling or by triggering inherent immune effector mechanisms. For tumour-associated antigens these target antigens may not be tumour-specific, but normal cellular macromolecules expressed at increased density or in an atypical context on the cancer cells. This type of approach is being used for example against anti-epidermal growth factor receptor (Cetuximab, IMC C225 and Bevacizumab) which are both currently undergoing phase III studies in a number of different solid tumour sites.

A novel group of mAb which are emerging as effective anti-cancer therapies are able to regulate antigen presentation and CD8⁺ / cytotoxic T cell (CTL) responses. Here irradiation causes tumour cell death, releasing critical tumour antigens whilst the mAb, such as anti-CD40, stimulate a CTL response against tumour antigen. Combining irradiation with immunomodulatory mAb in this way may also provide a powerful new approach to the treatment of cancer and form the basis of the second domain of projects within the laboratory-based group.

Main focus of laboratory work

The two main foci of the laboratory work are the optimisation of RIT in haematological malignancies and using irradiation with mAb that induce immunoregulation. In the first project, the roles of mAb as both vectors in delivering irradiation to tumours and also in direct cancer cell killing are further explored. This work has attracted much interest and was featured in New Scientist (9 April 2005) in an article on cancer research entitled "The next wave - double barrelled attack".

In the second project, mAbs are used to augment T-cell responses to tumour by blocking or stimulating co-receptors in the immune system. This project further defines the factors which are important in combining irradiation and immunoregulatory mAb. The aim of this work is to specifically investigate whether the effective clearance of tumour and the subsequent host immune responses observed are mediated through enhanced tumour cell antigen presentation. The results from our studies directly inform future clinical studies as well as the clinical studies underway providing new avenues of investigation for our experimental studies.

Translational research

An integral part of the targeted therapy group's work is translational research and there are a number active collaborations with clinical and research groups on the Manchester Cancer site.

 

Staff members