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Oblimersen Sodium and Rituximab in Treating Patients With Recurrent B-cell Non-Hodgkin Lymphoma

ABSTRACT: The goal of this clinical research study is to learn if the combination of oblimersen sodium and rituximab can help to shrink or slow the growth of the tumor in patients with B-cell non-Hodgkin’s lymphoma who have not responded to earlier treatment. Oblimersen Sodium is an investigational drug. The safety of this combination treatment will also be studied

DISEASE(S): Extranodal Marginal Zone B-cell Lymphoma Of Mucosa-associated Lymphoid Tissue,Recurrent Grade 3 Follicular Lymphoma,Lymphoma, Large B-cell, Diffuse,Lymphoma, Large-cell, Immunoblastic,Waldenström Macroglobulinemia,Recurrent Adult Lymphoblastic Lymphoma,Small Intestine Lymphoma,Recurrent Grade 1 Follicular Lymphoma,Testicular Lymphoma,Splenic Marginal Zone Lymphoma,Lymphoma, Mantle-cell,Recurrent Adult Immunoblastic Large Cell Lymphoma,Recurrent Adult Burkitt Lymphoma,Lymphomatoid Granulomatosis,Plasmablastic Lymphoma,Precursor Cell Lymphoblastic Leukemia-lymphoma,Lymphoma, B-cell, Marginal Zone,Burkitt Lymphoma,Lymphoma,Recurrent Adult Diffuse Small Cleaved Cell Lymphoma,Nodal Marginal Zone B-cell Lymphoma,Recurrent Small Lymphocytic Lymphoma,Recurrent Adult Diffuse Mixed Cell Lymphoma,Recurrent Marginal Zone Lymphoma,Recurrent Grade 2 Follicular Lymphoma,Lymphoma, Follicular,Waldenstrom Macroglobulinemia,Recurrent Adult Grade Iii Lymphomatoid Granulomatosis,Lymphoma, Non-hodgkin,Recurrent Adult Diffuse Large Cell Lymphoma,Intraocular Lymphoma,Leukemia, Lymphocytic, Chronic, B-cell,Lymphoma, B-cell,Cutaneous B-cell Non-hodgkin Lymphoma,Recurrent Mantle Cell Lymphoma

PROVIDER: 2008837 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Purpose: Despite recent advances in the treatment of patients with aggressive lymphomas, still a significant fraction of patients will succumb to their disease. Thus, novel therapeutic strategies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects. Experimental Design: Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Results: Overall, three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 2/11 cell lines were primarily sensitive to tafasitamab and 2/11 were predominantly sensitive to rituximab treatment, the combination of tafasitamab and rituximab resulted in enhanced cell death in 7/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combinatorial approach of the two antibodies resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model. Conclusions: This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to antibody mono treatment in models of aggressive B-cell lymphoma in vitro and in vivo. Translational Relevance: The immunochemotherapy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains the standard of care for newly diagnosed DLBCL patients. However, 30-40% of patients are refractory or relapse after initial response to the immunochemotherapy, indicating a high-unmet medical need for these patients. Tafasitamab and rituximab target the B-cell surface proteins CD19 and CD20, respectively, and both antibodies feature overlapping modes of action , namely direct cytotoxicity, ADCC and ADCP. In this study, we show that the combination of tafasitamab and rituximab had additive and synergistic efficacy both in vitro and in vivo. Our findings shed new light on the underlying mechanism of the combination of both antibodies and lay the ground to translate the results into improved outcome for patients with aggressive lymphoma in future clinical trials.

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Oblimersen Sodium and Rituximab in Treating Patients With Recurrent B-cell Non-Hodgkin Lymphoma

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