A Phase 1, Open-Label, Multicenter Study of Treatment with ACE1831, Comprised of Allogeneic Gamma Delta T Cells Conjugated to an Anti-CD-20 Antibody, in Patients (Pts) with B-Cell Relapsed/Refractory Non-Hodgkin's Lymphoma (R/R NHL)
Authors: Stevens Don A. , Romancik Jason T , Patel Rushang D. , Nair Ranjit , Pan Janet , Chien Stephanie , Olorunyomi Ifeoluwapo , Tang Sai-Wen , Kelley Heather , Liu Jerry , Kurman Michael 
Published: December 2024

Introduction
ACE1831, an off-the-shelf cellular therapy comprised of allogeneic gamma delta T (γδT) cells conjugated to anti-CD20 antibody via DNA linkers using bio-orthogonal chemistry, is being studied in a first-in-human, Ph1 study (NCT05653271) in pts with B-cell R/R NHL.
Methods
This is an open-label, multicenter, single, ascending dose, 3+3, Phase 1 study of the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of ACE1831 at dose levels 0.3, 0.6 and 1.0 billion [B] cells administered alone or in combination with obinutuzumab. Pts with R/R NHL who had received ≥ 2 prior lines of therapy receive a single infusion of ACE1831 (w/w/o obinutuzumab) following lymphodepletion with cyclophosphamide and fludarabine. The primary endpoints include the incidence of adverse events (AEs), dose-limiting toxicities (DLTs), the determination of the recommended Phase 2 dose, as well as ACE1831 persistency, immunogenicity, biomarker induction, and preliminary efficacy per the International Working Group Response Criteria. ACE1831 persistence was evaluated by flow cytometry analysis using anti-Vδ2 TCR (γδT marker) antibody recognizing both patients' γδT cells and ACE1831 in all subjects.
Results
As of June 13, 2024, 5 pts received a single dose of 0.3 B cells. Four pts had DLBCL and 1 had high-grade B-cell NHL. Four pts were male and 1 female; 4 pts were White and 1 was African-American. The median age was 65 (range: 32 - 76), and pts had a median of 5 prior lines of therapy (range: 2-7), including 4 pts that had received prior CAR-T therapy. Two patients had bulky disease and 2 had extra-nodal disease. No DLTs were reported. The most frequently observed treatment emergent AEs (TEAEs) were neutrophil, platelet, and white blood cell count decreased (n=5, 4, and 3, respectively), anemia (n=3) and fatigue (n=3). Most of these AEs were considered secondary to lymphocyte depletion chemotherapy, and none were considered related to ACE1831 alone. No ACE1831 serious TEAEs were reported, and no cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft vs. host disease (GvHD) was observed. One pt with low-volume disease had a complete response that has persisted beyond 180 days; 3 pts had stable disease; and 1 patient had progressive disease. The percentage of γδT cells in CD3 + T cell population peaked between Day 5 to Day 11 post ACE1831 infusion and decreased after the peaks. Cytokines IFNγ, TNFα, IL-6, IL-8, IL-10, and IL-2 were monitored in pts treated with ACE1831 during the DLT period. The peak levels of IFNγ, TNFα, IL-6, IL-8, or IL-10 were observed between Days 3 and 22. The IL-6 peak levels in ACE1831-treated pts were markedly lower than those in CAR-T-treated pts with CRS, suggesting less CRS potential. Anti-drug antibody responses to ACE1831 were monitored by flow cytometry analysis in four pts during the DLT period with Day -5 levels as baseline and there were no increases of anti-ACE1831 antibodies observed.
Conclusions
Preliminary data in 5 pts showed no DLTs, ACE1831-related SAEs, as well as no CRS, ICANS, or GvHD in single dose of 0.3B cells in 5 pts. Dose escalation will continue including 0.6 and 1B cells, with updated clinical data to be provided.
Clinical trial identification
NCT05653271