Lowry, LM; (2017) Impact of constitutional polymorphisms in immune effector mechanisms on clinical response to rituximab therapy in patients with follicular lymphoma. Doctoral thesis , UCL (University College London).

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Abstract

The anti-CD20 monoclonal antibody, rituximab, has very significantly altered management and prognosis in patients with various B-cell malignancies, including follicular lymphoma. However, some patients respond less well to rituximab or become resistant to it. A better understanding of the mechanisms of action of rituximab in cancer patients and reasons for treatment failure could lead to optimal use of the drug and the design of more effective monoclonal antibodies in the future. It has been suggested that constitutional polymorphisms in immune effector mechanisms may explain some inter-individual differences in rituximab effectiveness. Particularly, a polymorphism in the Fc receptor IIIA has been found in several small studies to be correlated with clinical response to rituximab. A large, multicentre trial in newly diagnosed, advanced stage but asymptomatic follicular lymphoma randomised patients to receive up-front rituximab monotherapy or to watchful waiting. This cohort of patients provided an excellent opportunity to examine the possible effect of this, and other polymorphisms. Patient samples were tested by PCR and restriction enzyme digestion for this polymorphism in Fc receptor IIIA (FCGR3A-V158F), and linked with the cleaned clinical database. Other constitutional polymorphisms in Fc receptors and the complement pathway have been suggested to play a role in rituximab response. Additional work determined polymorphism status for the same patient cohort for FCGR2A-H131R, FCGR2B-I232T, C1QA-Gly70GGG/GGA and C3-R102G. In summary, there was no convincing evidence of a large effect of any of the polymorphisms studied. In particular, the FCGR3A-158V allele, considered by many to predict rituximab response on the basis of in vitro work and small, published series, was found to have no effect in this larger study. This has implications for future antibody design and usage, and interpretation of small pharmacogenetic response studies in general.

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