Epcoritamab induces potent anti-tumor activity against malignant B-cells from patients with DLBCL, FL and MCL, irrespective of prior CD20 monoclonal antibody treatment

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.

The Tumor Microenvironment in Follicular Lymphoma: Its Pro-Malignancy Role with Therapeutic Potential

“…T-cell activation was significantly lower in patients with higher tumor HVEM expression. However, no relationship was observed between HVEM expression and epcoritamab-dependent cytotoxicity [87]. This corroborates the previous findings that frequencies of polyfunctional alloreactive T-cell, which was defined combining intracellular measurements of IFN-γ, IL-2, or TNF-α and surface expression of CD107a, after stimulation with FL B cells harboring dual aberrations (for example, homozygous deletions, nonsense mutations and deletions) were higher than FL B cells with wild-type TNFRSF14 [83].…”

“…An ongoing first-in-human clinical trial on epcoritamab showed a favorable safety profile and preliminary efficacy data indicating encouraging antitumor activity as a single agent in patients with R/R B-NHLs, including FL [86]. Noteworthy, van der Horst et al [87] found no association between T-cell activation and tumor expression of CD20, PD-L1, or HLA-DR. Activation of allogenic CD4 + and CD8 + T cells was the highest in patients that showed low expression of HVEM in B-NHL cells, including FL. T-cell activation was significantly lower in patients with higher tumor HVEM expression.…”

Primary Mediastinal B-Cell Lymphoma: Novel Precision Therapies and Future Directions

“…Epcoritamab has been reported to exert strong anti-tumor activity against primary tumor cells present in lymph node biopsies of patients with rrB-NHL, even if this group of patients has received CD20 monoclonal antibody treatment. The results of this study allow us to speculate that epcoritamab may be used for the treatment of newly diagnosed or rrB-NHL patients (105). In summary, studies investigating bs-mAbs in lymphoma mostly involve rrB-NHL.…”

Integration of cell therapies and bispecific antibodies into the treatment pathway of relapsed diffuse large B-cell lymphoma

“…Epcoritamab has shown promising preclinical efficacy with high rates of in vitro cytotoxicity activity against malignant B-cells from patients with non-Hodgkin lymphomas including DLBCL. 39 In a phase I/II trial, it was shown to have an overall response rate (ORR) of 66.7%. Most importantly, patients who already had CAR-T therapy have responded to this BSA with no reported grade 3 or above toxicity.…”