Study of the efficacy of novel bispecific antibodies targeting immune checkpoints in a 3D model of B non‐Hodgkin lymphoma

Despite therapeutic advances, follicular lymphoma (FL) remains an incurable disease. In addition to tumour-specific genomic alterations, the tumour microenvironment plays an essential role in the progression of the disease by participating in immuno-escape mechanisms. Among them, the PD-1/PDL1 axis has been widely studied but the efficacy of anti-PD-1 remains limited in FL suggesting additional immune escape mechanisms such as LAG-3. In order to decipher this issue, we tested the efficacy of a bispecific antibody targeting both PD1 and LAG-3 ICPs in a 3D model of FL co-cultured with PD-1/LAG-3 expressing γαμμαδελταT cells. Therefore, we studied γαμμαδελταT cells infiltration and measured their activation as well as tumour B cell depletion by flow cytometry and high throughput 2D/3D analyses. Our results showed that aPD-1xLAG-3 bispecific antibody enhances CD20-TCB efficacy by increasing γδT cells infiltration into 3D model and their activation as attested by an increase of Granzyme B and IFNγαμμα secretion. Consequently, a decrease of 3D area correlated with a potent B cell depletion was observed after combination treatment. Finally, we observed that percent of PD-1+/LAG3+ γαμμαδελταT cells negatively correlates with drug efficacy. 3D cell cultures from FL biopsies (Patient-Derived Lymphoma Spheroids-PDLS) will allow us to confirm these results in relevant preclinical models. The research was funded by: This research collaboration was supported through the imCORE network on behalf of F.Hoffmann-La Roche. Keywords: Immunotherapy, Indolent non-Hodgkin lymphoma, Risk Models Conflicts of interests pertinent to the abstract. F. Bouquet Employment or leadership position: Roche employee C. Fonseca Employment or leadership position: Roche employee S. Herter Employment or leadership position: Roche employee Stock ownership: roche L. Codarri Employment or leadership position: Roche employee R. McCord Employment or leadership position: Genentech employee E. Chiang Employment or leadership position: Genentech employee F. Morschhauser Consultant or advisory role: Roche, Gilead, Genmab, Novartis, Abbvie Honoraria: Chugai (scientific lectures) C. Laurent Educational grants: Janssen