A murine proof-of-concept study of polatuzumab vedotin in combination with venetoclax in experimental therapy of BCL2-positive aggressive lymphomas

We evaluated the in vivo efficacy of polatuzumab vedotin (POLA), administered as a single agent or in combination with venetoclax (VEN), in relapsed/refractory (R/R) mantle cell lymphoma (MCL) and BCL2-positive diffuse large B-cell lymphoma (DLBCL). In addition, we investigated the mechanisms underlying acquired resistance to POLA in vivo. Experimental therapy was assessed using a panel of 8 cell line-derived xenografts (CDXs) and 16 patient-derived xenografts (PDXs) representing MCL and DLBCL. Bulk transcriptomic profiling was performed on 7 paired tumor samples obtained from POLA-resistant tumors (generated in mice following repeated POLA-based treatments) and their corresponding untreated controls. POLA demonstrated robust single-agent antitumor activity in vivo, including in PDX models derived from patients with ibrutinib-resistant MCL. In the majority of tested PDX models, the combination of POLA and VEN produced synergistic antitumor effects without evidence of measurable toxicity. CD79B expression levels did not correlate with POLA efficacy. Following POLA treatment failure, downregulation of CD79B was observed in only a minority of models, indicating the involvement of additional mechanisms of acquired resistance. Bulk transcriptomic analysis of 7 paired POLA-resistant versus untreated tumors identified a conserved gene expression signature across all models, comprising 523 downregulated and 284 upregulated genes. This signature likely reflects core pathways associated with POLA resistance and highlights potential novel therapeutic vulnerabilities. These findings strongly support further clinical investigation of POLA in combination with VEN as a BCL2- and MCL1-targeting therapeutic strategy in patients with R/R MCL and BCL2-positive R/R DLBCL.