PROTEOMIC PROFILING IDENTIFIES GRANZYME B INHIBITOR SERPIN B9 AS MEDIATOR OF RESISTANCE TO CAR T‐CELL AND BISPECIFIC ANTIBODY TREATMENT IN NODAL B‐CELL LYMPHOMA

Introduction: Treatment options for relapsed or refractory (r/r) B-cell non-Hodgkin lymphomas (B-NHL) have broadened towards T-cell engaging therapies, including CD19-targeting chimeric antigen receptor T-cells (CD19-CAR) and bispecific antibodies (CD19-BsAb). Although CD19-CAR CD19-BsAb induce durable responses in some r/r B-NHL patients, response remains heterogenous a significant proportion of patients experience insufficient relapse. A thorough understanding tumor-intrinsic mechanisms resistance is crucial the clinical improvement immunotherapy. Methods: Aiming to identify lymphoma cell-inherent that impair therapy, we quantified in-vitro 46 cell lines 3rd generation CD19-BsAb. Response was measured using high-throughput flow cytometry-based assay. In parallel, were subjected proteomic profiling protein abundance regressed on order determinants response. We further combined treatment with clinically relevant drugs assessed how killing cells expansion altered. Results: highly heterogeneous across entities, but not significantly linked their proliferation rate CD19 expression. Integration profiles revealed Serpin B9, endogenous inhibitor effector molecule granzyme B, associated poor This finding validated overexpression knock-out models. Overexpression SERPINB9 indeed attenuated CD19-BsAb, while its rendered more sensitive. The observed changes susceptibility T-cell-mediated cytotoxicity upon modulation expression independent donor activation markers. sought improve specifically samples high found immune checkpoint inhibitors lenalidomide enhanced CAR increased cells. addition, vorinostat antibody-drug-conjugate polatuzumab vedotin killed without affecting expansion. However, Keywords: aggressive lymphoma, immunotherapy, indolent No conflicts interests pertinent abstract.