AUTHOR=Patra-Kneuer Maria , Chang Gaomei , Xu Wendan , Augsberger Christian , Grau Michael , Zapukhlyak Myroslav , Ilieva Kristina , Landgraf Karin , Mangelberger-Eberl Doris , Yousefi Kasra , Berning Philipp , Kurz Katrin S. , Ott German , Klener Pavel , Khandanpour Cyrus , Horna Pedro , Schanzer Jürgen , Steidl Stefan , Endell Jan , Heitmüller Christina , Lenz Georg TITLE=Activity of tafasitamab in combination with rituximab in subtypes of aggressive lymphoma JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1220558 DOI=10.3389/fimmu.2023.1220558 ISSN=1664-3224 ABSTRACT=Background

Despite recent advances in the treatment of aggressive lymphomas, a significant fraction of patients still succumbs to their disease. Thus, novel therapies 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.

Methods

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 in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).

Results

Three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 1/11 cell lines was primarily sensitive to tafasitamab and 2/11 to rituximab, the combination resulted in enhanced cell death in 8/11 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 combination resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model.

Conclusion

This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to single-agent treatments in models of aggressive B-cell lymphoma in vitro and in vivo.