Exposure to epcoritamab is associated with improved T-cell functionality and dynamic changes in CD8+ T-cells in diffuse large B-cell lymphoma: Insights from epcore NHL-6

Abstract INTRODUCTION: Epcoritamab (epcor) is a subcutaneously (SC) administered bispecific T-cell engager (CD3-BsAb TCE) approved for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of therapy. Functionality of the immune compartment may impact rates and duration of response. Here, we report the clinical outcome of epcor monotherapy administered in the outpatient setting in DLBCL and show changes in clonally reactive T-cells with improved functional states linked to long-term response. Methods: Patients in the EPCORE NHL6 phase 2 trial (NCT05451810) received epcor in 28-day cycles (C): two C1 step-up doses (0.16mg, 0.8mg) then full dose at C1D15 and thereafter (48mg); C1-3, QW; C4-9, Q2W; C≥10, Q4W. Responses were investigator-assessed per Lugano criteria. Multi-parameter flow cytometry, ex vivo cytotoxicity, cytokine and T-cell activation induced by epcor were tested in the presence of a CD20-expressing tumor cell line (Jeko-1) using peripheral blood mononuclear cells (PBMCs) collected at baseline and after 2, 4, 5, and 7 cycles of epcor treatment from n=43 patients. PBMCs from samples collected pre- and on-treatment in a subset of patients that achieved response (complete response [CR]/partial response [PR]; n=7) were evaluated using Single-cell Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq) and single-cell T-cell receptor (TCR) repertoire analysis. RESULTS At the 15 January 2025 cutoff, 92 patients received ≥1 epcor dose (response and adverse events reported previously [Vaidya R, et al. SOHO 2025]). The overall response rate (ORR) for the 92 patients was 62.0% (95% CI: 51.2%, 71.9%) and the CR rate (CRR) was 42.4% (95% CI: 32.1%, 53.1%), which was similar in the subset of patients (n=43) with immune profiling (ORR, 62.8% [95% CI: 46.7%, 77.0%]; CRR, 44.2% [95% CI: 29.1%, 60.1%]). Ex vivo functional studies showed significant improvement in cytotoxic activity in a time-dependent and T-cell-dependent manner with higher proportions ofCD3 T-cells expressing activation and proliferation markers (CD25, P=.008; CD69, P=.041; Ki67, P=.001) in longitudinal samples from patients who achieved CR (n=13) vs patients with progressive disease (PD; n=10). UMAP analysis of flow cytometry data identified an accumulation of Tbethigh effector memory CD8 T-cells expressing granzyme B (P=.060) and a significant decrease (P=.036) in CD8+ T-cells with a senescence phenotype (CD28low, CD27low,CD57+ TEMRA cells positive for β-galactosidase) in CR patients. These changes were associated with improved ex vivo T-cell cytotoxic function in patients achieving a CR. Sorting experiments demonstrated that the ex vivo cytotoxic effects of epcor is primarily mediated by the non-senescent (CD8+CD57-) T-cell population. Preliminary CITEseq analysis showed that circulating CD8 T-cells, including CD8 effector memory (TEM), terminally differentiated TEM cells that express CD45RA (TEMRA), and effector cells, were activated and maintained a low exhaustion status during epcor treatment. Single-cell TCR repertoire analysis showed overlap of TCR sequences between baseline and on-treatment samples and examples of TCR clone expansion with epcor treatment among responders. CONCLUSION These findings highlight the immunologic impact of epcor treatment, marked by a progressive increase in functionally active CD8+ T cells with examples of increased TCR clonality and a reduction in senescent T-cell populations, notably without evidence of emerging dysfunction. These data provide insight into the mechanism of action of epcor and support its continued development as a transformative therapy in B-cell lymphoma.