Tumour Burden Influence on Individual Rituximab Exposure and Response: Pharmacokinetic - Pharmacodynamic Approach by Using a Syngenic Bioluminescent Murine Model.

Immunotherapy with the humanised monoclonal anti-CD20 antibody rituximab represents an interesting therapeutic option for patients with B-cell Non-Hodgkin’s Lymphoma. Early clinical trials have shown that rituximab exposure was variable in patients receiving similar doses and that clinical response was related to rituximab concentrations. The aim of our study was to evaluate the influence of tumour burden on rituximab exposure and response to treatment. 8.10³ cells of murine T-lymphoma cells (EL4) transduced with human CD20 cDNA (EL4-hCD20) and stably transfected with luciferase plasmid (EL4-hCD20-luc) were injected to C57Bl6J mice by i.v. route. Tumour detection, disease dissemination and progression were evaluated by in vivo bioluminescence imaging. Quantitative imaging analysis was performed after background noises and cosmic rays elimination. Rituximab concentrations were carried out by ELISA method. One dose of rituximab was injected thirteen day after lymphoma cell infusion, a time need for the development of disseminated disease. In the control group without rituximab, all mice developed disseminated lymphoma and died within 30 days whereas we found a significant dose/response relationship with increased doses of rituximab (from 150 μg to 1000 μg). At 500μg of rituximab, we found an important variability in response to treatment with about 23% of mice cured, 59% in partial response and 18% with progressive diseases. For all of these mice, tumour burden, determined before rituximab injection were calculated taking into account their size and bioluminescent activities corrected by the absorption coefficient of light according to the site localisation. Thus, we have demonstrated a significant correlation between tumour burden and response to rituximab and survival. Mice with the lower tumour burden having increased remission rates and survival. Using a pharmacokinetic-pharmacodynamic (PK-PD) model we also demonstrated that tumour burden influence rituximab exposure and response. There is a connection between tumour burden and rituximab efficiency (r² = 0.938). Such results should have consequences for the rituximab use in human and in pre-clinical assessment of new anti-CD20 antibodies. D.D. is supported by a grant from Région Centre. This study has been supported by Association pour la Recherche contre le Cancer (Grant number: 3229), by the Institut National du Cancer and Cancéropôle Grand Ouest (MAb IMPACT - IMProving ACTivation of FcγRIIIa-expressing effector cells, pharmacogenetic-based optimisation of monoclonal antibody therapy for cancer-federative project) and by Roche France.