Abstract 1788: Enhanced in vitro/in vivo cytotoxicity against Burkitt lymphoma/primary mediastinal large B cell lymphoma by polatuzumab vedotin (hu- anti-CD79b-vc-MMAE, PV) alone or in combination with obinutuzumab
Authors: Tiwari Aradhana Awasthi , Edani Dina , Azmy Christeen , Ayello Janet , Klein Christian , Cairo Mitchell S. 
Published: August 2018

Background: Mature B-NHL, including Burkitt lymphoma (BL) and primary mediastinal large B cell lymphoma (PMBL) express CD20+/CD79b+ and have an excellent prognosis, however, subset of patients relapse secondary to chemoimmunotherapy resistant disease and have a dismal prognosis (≤ 20% 5 yr. EFS, Cairo et al. Blood. 2007; Gerrard/Cairo et al., Blood, 2013, Goldman/Cairo et al. Leukemia, 2013). PV has been demonstrated to possess significant preclinical activity against indolent CD79b+NHL (Polson et. al.Can. Res.2009). We previously observed that obinutuzumab (Anti-CD20 mAb) significantly enhanced cell death and increased overall survival against BL (Awasthi/Cairo et al., BJH 2015) in xenografted NSG mice. However, additive/synergistic effects of PV with obinutuzumab against mature PMBL/BL are unknown.

Objective: To determine the efficacy of the PV or obinutuzumab/RTX alone or in combination against PMBL and rituximab (RTX) sensitive/resistant BL cell lines.

Methods: Raji4RH (provided by M. Barth, MD, Roswell Park Cancer Institute) and Raji/ Karpas1106P (ATCC, USA) were cultured in RPMI. Tumor cells were incubated with PV, and/or anti-CD79b, MMAE (generously supplied by Genentech Inc.) with obinutuzumab /rituximab (100ug/ml) for 4 hr with NK cells at 10:1 E: T ratio and cytotoxicity was determined by DELFIA cytotoxicity assay. Six to 8 week old female NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ), were divided into 5 groups: PBS, isotype control, PV, antiCD79B mAb and MMAE (5mg/kg). Mice were xenografted with intravenous injections of Luc+ BL and PMBL cells and tumor burden was monitored by IVIS spectrum system.

Results: OS of mice receiving PV alone was significantly increased compared to antiCD79b or isotype control in Raji (35.5 vs.17 vs.19.5 days, p=0.0001, 0.0003), Raji4RH (50 vs.18 vs.18.5 days, p=0.0001, 0.0001) and Karpas1106P (150 vs 89 vs 64 days, p=0.03, 0.003), respectively. Obinutuzumab+NK, rituximab+NK compared to PV+NK cells significantly enhanced cell lysis in Raji, 65.9±2.4% vs. 38.9±5.4% vs. 44.24±8.1% (p=0.001 & p=0.001), Raji4RH, 52.8±9.4% vs. 16.04±7.2% vs.47.0±8.2% (p=0.03 & p=NS) and Karpas1106P, 66.10±5.3% vs.48.2±3.9% vs. 61.6±10.06% (p=0.004 & NS), respectively. PV+ obinutuzumab+NK, significantly improved cytotoxicity compared to PV+ rituximab+NK in Raji, 93.6±6.1% vs 79.9±5.3% (p=0.007), Raji4RH, 78.07±2.05% vs 63.5±0.16% (p=0.004) and Karpas1106P, 88.3±6.3 %vs.73.03±3.03% (p=0.003), respectively.

Conclusion: Our preliminary data indicates that PV significantly increased survival in BL and PMBL NSG xenografts compared to anti-CD79b Ab alone. Furthermore, PV in combination with obinutuzumab significantly enhances cytotoxicity in BL and PMBL compared to obinutuzumab or PV alone.

Citation Format: Aradhana Awasthi Tiwari, Dina Edani, Christeen Azmy, Janet Ayello, Christian Klein, Mitchell S. Cairo. Enhanced in vitro/in vivo cytotoxicity against Burkitt lymphoma/primary mediastinal large B cell lymphoma by polatuzumab vedotin (hu- anti-CD79b-vc-MMAE, PV) alone or in combination with obinutuzumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1788.