Abstract 5390: The combination of polatuzumab vedotin with rituximab increases antitumor activity against polatuzumab vedotin-refractory lymphoma

Abstract Introduction; Polatuzumab vedotin (Pola) is an antibody-drug conjugate which targets B-cell antigen CD79b and delivers monomethyl auristatin E (MMAE). The randomized phase 1b/2 study (GO29365) showed that the complete response rate in the Pola plus bendamustine (B) and rituximab (R) (Pola+BR) arm was significantly higher than the control BR arm in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) (Sehn et al., 2020). Based on these results, the Pola+BR has been approved in various countries. However, it is not clear whether the Pola combination regimen is effective in patients with Pola-refractory lymphoma. Investigating this could provide insight into effective treatment strategies against r/r DLBCL. Therefore, we analyzed the combination effect of Pola+R on complement-dependent cytotoxicity (CDC), one of the major mechanisms of R, in the DLBCL cells with low sensitivity to Pola as a model for Pola-refractory lymphoma (referred to as Pola-refractory cells).Methods. For the CDC assays, calcein-AM stained cells were incubated with R in medium containing 15% normal human serum, and fluorescence intensity was measured. Expression levels of protein were determined by flow cytometry or immunoblotting. For in vivo experiments, human SU-DHL-8 cells were injected subcutaneously into C.B-17/Icr-scid/scidJcl mice. Human IgG, Pola (2 mg/kg), or R (30 mg/kg) was administered intravenously on Day 1. Results: We found that three-day-pretreatment with Pola enhanced cell-surface expression of CD20 and R-induced CDC sensitivity in SU-DHL-8 Pola-refractory cells in vitro. A similar combination effect was observed in HT and SU-DHL-2 cells. Pola also increased CD20 expression on the SU-DHL-8 xenografted tumors and significantly enhanced antitumor activity by combination with R in this model. Both AKT and MEK specific inhibitors attenuated the Pola-induced increase of CD20 and CDC sensitivity, suggesting that phosphorylation of AKT and ERK after Pola treatment was required for this combination efficacy. To examine which part of Pola is responsible for regulating these signals, we used anti-human CD79b antibody SN8, a parental antibody for Pola, and its payload MMAE. SN8 increased the phosphorylation of AKT but inhibited the phosphorylation of ERK. In contrast, MMAE potentiated phosphorylation of ERK but weakly attenuated the phosphorylation of AKT. Taken together, these results suggest that Pola, which consists of SN8 and MMAE, may cancel the negative effect of each, and enhance CD20 expression and CDC sensitivity. Conclusion: In these Pola-refractory cells, pretreatment with Pola enhanced CD20 expression and R-induced CDC sensitivity. Combination treatment of Pola+R enhances antitumor activity in the Pola-refractory xenograft mouse model. These results provide a novel rationale for the combination of Pola+R in Pola-refractory lymphoma. Citation Format: Natsumi Kawasaki, Yasushi Yoshimura, Shigeki Yoshiura. The combination of polatuzumab vedotin with rituximab increases antitumor activity against polatuzumab vedotin-refractory lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5390.