Bispecific antibodies in Lymphoma: Microenvironmental profiling to predict treatment response and uncover immunogenic resistance mechanisms
Redirection of autologous T-cells through bispecific antibodies (BsAb) is an important therapeutic principle to treat B cell lymphomas. Treatment response however is heterogeneous, highlighting the need for a better understanding of resistance mechanisms and biomarkers for response prediction. Both tumour intrinsic, e.g. genetic and epigenetic alterations, and extrinsic factors, e.g. composition and functional state of the lymph node (LN) microenvironment, determine the response to BsAb. We aim to identify, understand and exploit them to improve treatment strategies. Aim 1: Improve our understanding of the LN microenvironment of relapsed and refractory B cell lymphomas. Composition and biological state of LN derived microenvironmental cells will be characterised at multiple levels by single-cell transcriptomics (CITE-Seq), DNA mutation analysis and proteomics. To characterise the spatial organisation, including T-cell engagement, we will analyse matched FFPE tissues using multiplexed immunofluorescence. Aim 2: To understand how lymphoma cell characteristics and LN microenvironment influence the activity of BsAb, we will perform functional ex-vivo response profiling ofdrug BsAb combinations in increasingly complex tumour models. Aim 3: We will characterise the most relevant microenvironmental features from Aims 1&2 in patients treated with BsAb. With support of the German, French and Italian Lymphoma societies we will assemble patient cohorts to identify biomarker signatures for response or resistance to BsAb in vivo. To improve patient stratification we will transfer these biomarkers to a clinically applicable assay. All generated data will be centrally managed with shared computational data analysis workflows jointly usable by all partners, enabling rapid, multi-approach, transparent analyses. Altogether, we aim to expand the understanding of the lymphoma microenvironment, uncover treatment response markers and enable improved T-cell based immunotherapies
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.