Abstract
Epcoritamab (DuoBody-CD3xCD20, GEN3013) is a novel bispecific IgG1 antibody redirecting T-cells toward CD20+ tumor cells. Here, we assessed the preclinical efficacy of epcoritamab against primary tumor cells present in the lymph node biopsies from newly diagnosed (ND) and relapsed/refractory (RR) B-NHL patients. In the presence of T-cells from a healthy donor, epcoritamab demonstrated potent activity against primary tumor cells, irrespective of prior treatments, including CD20 mAbs. Median lysis of 65, 74, and 84% were achieved in diffuse large B-cell lymphoma (n = 16), follicular lymphoma (n = 15), and mantle cell lymphoma (n = 8), respectively. Furthermore, in this allogeneic setting, we discovered that the capacity of B-cell tumors to activate T-cells was heterogeneous and showed an inverse association with their surface expression levels of the immune checkpoint molecule Herpesvirus Entry Mediator (HVEM). In the autologous setting, when lymph node (LN)-residing T-cells were the only source of effector cells, the epcoritamab-dependent cytotoxicity strongly correlated with local effector cell-to-target cell ratios. Further analyses revealed that LN-residing-derived or peripheral blood-derived T-cells of B-NHL patients, as well as heathy donor T-cells equally mediated epcoritamab-dependent cytotoxicity. These results show the promise of epcoritamab for treatment of newly-diagnosed or relapsed/refractory B-NHL patients, including those who became refractory to previous CD20-directed therapies.
Highlights
Introduction TheB-cell specific marker CD20, which is expressed on all mature B-cells, but absent on hematopoietic stem cells, pro-B-cells and plasma cells[1], is an attractive target for the treatment of B-cell malignancies, including B-cell nonHodgkin lymphomas (B-NHL)
Using T-cells from a single healthy donor as effector cells, we explored the intrinsic sensitivity of tumor cells from different B-NHL subtypes to epcoritamab and their capacity to activate T-cells
We demonstrate that epcoritamab mediated high levels of cytotoxicity against tumor cells from patients with B-NHL (DLBCL, FL, and MCL)
Summary
B-cell specific marker CD20, which is expressed on all mature B-cells, but absent on hematopoietic stem cells, pro-B-cells and plasma cells[1], is an attractive target for the treatment of B-cell malignancies, including B-cell nonHodgkin lymphomas (B-NHL). We investigated the preclinical activity of epcoritamab using primary tumor cells obtained from lymph node (LN) or bone marrow (BM) biopsies samples of patients with diffuse large B-cell lymphoma (DLBCL; n = 16), follicular lymphoma (FL; n = 15) and mantle cell lymphoma (MCL; n = 8). The patients were newly diagnosed (ND) or relapsed/refractory (RR) to conventional treatment regimens, including anti-CD20 mAbs. We investigated (i) the intrinsic sensitivity of tumor cells to epcoritamab-dependent T-cell-mediated cytotoxicity and the capacity of tumor cells to activate T-cells, ii) whether type of malignancy and prior exposure to CD20-targeted therapy influenced their sensitivity, and (iii) the intrinsic capacity of tumor-associated Tcells to mediate epcoritamab-dependent cytotoxicity
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