Page 13 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

ANTIBODY-BASED TREATMENT IN CANCER 1
The scientific concept of a “magic bullet” to specifically eradicate disease, without harming the body, was developed by Paul Ehrlich (1854-1915) (1). Treatment of cancer with chemotherapy or radiotherapy does not meet these expectations as significant toxicity is caused by destruction of normal healthy cells.
In 1975, George Kohler and Cesar Milstein discovered a way to produce large numbers of identical, monoclonal antibodies (mAbs) directed against specific target antigens (2). This hybridoma technique allowed the development of rituximab, a chimeric mouse/human monoclonal antibody with binding specificity to the target antigen CD20. This target antigen is a transmembrane protein expressed on the surface of normal and malignant B cells. It was considered a suitable target antigen as absence of CD20 expression in B-cell non Hodgkin lymphoma at initial diagnosis is extremely rare (1-2%) (3). Although normal B cells are targeted as well, overall toxicity (e.g. increased infection risk) is limited and treatment with rituximab is usually well tolerated. Depletion of CD20-positive B-cells generally does not cause permanent side effects as mature plasma cells and B-cell progenitor cells do not express CD20.
In 1980, proof-of-principle of efficacy was demonstrated as the first patient receiving an anti-CD20 antibody showed a decrease in circulating tumor cells (4). Rituximab was the first therapeutic mAb in oncology and was initially approved in 1997 for the treatment of follicular lymphoma (5). Subsequently, rituximab was implemented in the treatment for all B-cell malignancies. The clinical impact has been found to be significant. For example, the 2-year overall survival of previously untreated elderly patients with diffuse large B cell lymphoma was 70% vs 57% for rituximab combined with chemotherapy versus chemotherapy alone (6).
“All that glitters is not gold”
Despite the initial response, patients often relapse (7). It remains unclear which patients will benefit from further treatment with rituximab. Various mechanisms of rituximab resistance have been proposed (8).
One mechanism is insufficient cell death after rituximab binds to CD20 (downstream effects). To increase cell death, novel, fully humanized, anti-CD20 mAbs have been developed: ofatumumab for increased complement-dependent cytotoxicity and obinutuzumab for increased antibody-dependent cellular cytotoxicity. Other approaches for increased efficacy include radio-immunotherapy
Introduction
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