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Abstract
Background Rituximab is widely used in the treatment of haematological malignancies, including chronic lymphoid leukaemia (CLL), the most common leukaemia in adults. However, some patients, especially those with high tumour burden, develop cytokine release syndrome (CRS). It is likely that more patients will develop therapy-linked CRS in the future due to the implementation of other immunotherapies, such as CAR T-cell, for many malignancies. Current methods for CRS risk assessment are limited, hence there is a need to develop new methods.
Methods To better recapitulate an in vivo setting, we implemented the unique human whole blood ‘loop’ system (figure 1)1 to study patient-specific immune responses to rituximab in blood derived from CLL patients.
Results Upon rituximab infusion, both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) profiles were evident in CLL patient blood, coincident with CLL cell depletion. Whereas B cell depletion is induced in healthy persons in the blood loop, only patients display B cell depletion coupled with CRS. With the exception of one donor who lacked NK cells, all other five patients displayed variable B cell depletion along with CRS profile. Additionally, inhibition of CDC or ADCC via either inhibitors or antibody Fc modification resulted in skewing of the immune killing mechanism consistent with published literature
Schematic of the blood loop assay. A-C preparation of blood loops, D. Loops are kept in motion by attaching to rotating wheel. The air bubble inside the loop drives blood circulation within the loops.
Conclusions Herein we have shown that the human whole blood loop model can be applied using blood from a specific indication to build a disease-specific CRS and immune activation profiling ex vivo system. Other therapeutic antibodies used for other indications may benefit from antibody characterization in a similar setting.
Reference
Fletcher EAK, Eltahir M, Lindqvist F, Rieth J, Törnqvist G, Leja-Jarblad J, Mangsbo SM. Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanism-of-action of immunotherapeutics. Int Immunopharmacol 2018 Jan;54:1-11.
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