Proteomic profiling identifies Serpin B9 as mediator of resistance to CAR T-cell and bispecific antibody treatment in B-cell lymphoma

Although T-cell-engaging therapies are highly effective in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL), responses are often not durable. To identify tumor-intrinsic drivers of resistance, we quantified in-vitro response to CD19-directed chimeric antigen receptor T-cells (CD19-CAR) and bispecific antibodies (BsAb) across 46 B-NHL cell lines and measured their proteomic profiles at baseline. Among the proteins associated with poor in-vitro response was Serpin B9, an endogenous granzyme B inhibitor. Knock-out of SERPINB9 in cell lines with high intrinsic expression rendered them more susceptible to CD19-CAR and CD19-BsAb. Overexpression in cell lines with low intrinsic expression attenuated responses. Polatuzumab, vorinostat, lenalidomide, or checkpoint inhibitors improved response to CD19-CAR, although independently of Serpin B9 expression. Besides providing an important resource of therapy response and proteomic profiles, this study refines our understanding of resistance in T-cell engaging therapies, and suggests clinically relevant combination regimes.