Abstract
Primary mediastinal large B-cell lymphoma (PMBL), a distinct mature B-cell lymphoma, expresses CD20 and has recently been successfully treated with the combination of a type I anti-CD20 monoclonal antibody, rituximab, with multiple combination chemotherapy regimens. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody (mAb), recognizing a unique CD20 extracellular membrane epitope with enhanced antibody dependent cellular cytotoxicity (ADCC) vs rituximab. We hypothesize that obinutuzumab vs rituximab will significantly enhance in-vitro and in-vivo cytotoxicity against PMBL. PMBL cells were treated with equal dose of obinutuzumab and rituximab for 24 hours (1–100 μg/ml). ADCC were performed with ex-vivo expanded natural killer cells at 10:1 E: T ratio. Mice were xenografted with intravenous injections of luciferase expressing Karpas1106P cells and treated every 7 days for 8 weeks. Tumor burden was monitored by IVIS spectrum system. Compared with rituximab, obinutuzumab significantly inhibited PMBL cell proliferation (p = 0.01), promoted apoptosis (p = 0.05) and enhanced ADCC (p = 0.0002) against PMBL. Similarly, in PMBL xenografted NOD scid gamma mice, obinutuzumab significantly enhanced survival than rituximab when treated with equal doses (p = 0.05). Taken together our results suggest that obinutuzumab significantly enhanced natural killer cytotoxicity, reduced PMBL proliferation and prolonged the overall survival in humanized PMBL xenografted NOD scid gamma mice.
Highlights
Primary mediastinal large B-cell lymphoma (PMBL) is a rare form of non-Hodgkin lymphoma representing < 5% of mature B-cell NHL (B-NHL) [1, 2]
Karpas1106P showed a significant increase in the expression of both CD20 mRNA and protein (Figure 1A and 1B) compared to Burkitt lymphoma (BL) (Raji) and Hodgkin lymphoma (HDLM-2) cell lines
Karpas-1106P cells were treated with obinutuzumab, rituximab and IgG-isotype and viable cells were quantified by MTS assay
Summary
Primary mediastinal large B-cell lymphoma (PMBL) is a rare form of non-Hodgkin lymphoma representing < 5% of mature B-cell NHL (B-NHL) [1, 2]. Obinutuzumab plus chlorambucil prolonged the OS or PFS and resulted in higher rates of complete response in patients with chronic lymphocytic leukemia (CLL) or coexisting conditions as compared to chlorambucil alone, or rituximab plus chlorambucil, respectively in the CLL11 clinical trial (NCT01010061b) [18]. The phase III iLLUMINATE trial (NCT02264574) demonstrated that obinutuzumab plus Ibrutinib is an efficacious combination therapy for previously untreated patients with CLL or small lymphocytic lymphoma [19]. Based on these exciting results, obinutuzumab in combination with chemotherapy has been approved for the treatment of untreated and rituximab refractory FL [16, 17] and CLL [19]. The pre-clinical and clinical efficacy of obinutuzumab compared to rituximab in patients with PMBL is currently unknown
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