Cross-linking of T cell to B cell lymphoma by the T cell bispecific antibody CD20-TCB induces IFNγ/CXCL10-dependent peripheral T cell recruitment in humanized murine model

Diffuse large B cell lymphomas (DLBCL) are a highly heterogeneous subtype of Non Hodgkin Lymphoma (NHL), accounting for about 25% NHL. Despite an increased progression-free survival upon therapy, 40–50% patients develop relapse/refractory disease, therefore there remains important medical need. T recruiting therapies, such as the CD20xCD3 bi-specific antibody CD20-TCB (RG6026 or glofitamab), represent novel approach to target all stages DLBCL, especially those that fail respond multiple lines treatment. We aimed better understanding molecular features related mode action (MoA) in inducing Target/T synapse formation and human recruitment tumor. To directly evaluate correlation between synapse, cytokine production anti-tumor efficacy using CD20-TCB, we developed innovative preclinical DLBCL vivo model allowed tracking dynamics by multiphoton intravital microscopy (MP-IVM). By ex approaches, revealed is strong stable synapses tumor cells, which dependent on dose LFA-1 activity but not FAS-L. Moreover, despite being molecule (194.342 kDa), observed intra-tumor CD20-TCB-mediated cell-tumor occur within 1 hour administration. These tight interactions, at least 72 hours post TCB administration, result cytotoxicity, resident proliferation peripheral blood into blocking IFNγ-CXCL10 axis, cells was abrogated, partially affecting treatment rely only proliferation. Altogether these data reveal CD20-TCB’s relies triple effect: i) fast induce cytotoxicity production, ii) iii) fresh core allow positive enhancement effect.