P22

Genetic reprogramming systems for spatiotemporally regulated expression of immune effectors by transferred B cells to cure chronic diseases

F AMIRACHE(1) S PERIAN(1) C COSTA(1) U HASAN(1) F L COSSET(1)

1:CIRI; Inserm U1111

Cancer is a major public health problem, causing around 10 million deaths a year. Available treatments have numerous side-effects and often require multiple interventions; hence, the need over the long term for novel, more effective, more specific and even targeted therapeutic alternatives. In this study, we evaluated the potential of a new synthetic circuits to reprogram B cells for therapeutic purposes.

Such circuits encode a “sensor” corresponding to a membrane-anchored B cell receptor (BCR) targeting a model antigen ovalbumin (OVA) or mesothelin (MSLN) that are ectopically transduced in reprogrammed  B cells to express BCRs specific to these antigens. The circuits also encode a “transducer”, which is a part of the NR4A1 promoter that can be induced by activated BCR, and “effector” molecules. When disease biomarkers  are bound to the ectopic BCR, recognized here as inducing signals for the synthetic circuits, the NR4A1 promoter is specifically activated, leading to the expression of effector molecules.

We demonstrated the complete activation of the circuits in B cells following recognition of tumor cells expressing the target antigens ex vivo. To take further characterize these circuits, we established a humanized mouse model grafted with these tumor cells and, subsequently, with reprogrammed B lymphocytes to mimic adoptive transfer of autologous cells in a preclinical context. After validation of this cancer model, we confirmed the homing of reprogrammed B cells to the tumor sites. The potential of reprogrammed B cells is currently being assessed in vivo by the implementation of a therapeutic effector transgene.