585 DENALI-1: a seamless phase 1/2 study of A2B395, a logic-gated, allogeneic, Tmod CAR T therapy, in patients with EGFR-expressing solid tumors with human leukocyte antigen-A*02 loss of heterozygosity

作者：Salman R. Punekar, Matthew L. Ulrickson, Jennifer M. Specht, Deborah Jean Lee Wong, J. Randolph Hecht, Marcela V. Maus, Patrick Grierson, John B. Sunwoo, Julian R. Molina, David G. Maloney, Kristen Spencer, Harry E Fuentes, Marco L. Davila, Sandip Pravin Patel, Ben Creelan, David B. Zhen, Jiaxin Niu, Dhauna Karam, Wendy J. Langeberg, Gabrielle Palluconi, Eric Ng, John S. Welch, William Y. Go, Kedar Kirtane, Rebecca Shatsky · 发表于：Regular and Young Investigator Award Abstracts · 年份：2025 · DOI：10.1136/jitc-2025-sitc2025.0585 · 被引用次数：1 · 研究领域：CAR-T cell therapy research、Monoclonal and Polyclonal Antibodies Research、HER2/EGFR in Cancer Research

Background Despite the success treating hematologic malignancies, chimeric antigen receptor T-cell (CAR T) therapies face challenges in solid tumors due to lack of targets that distinguish tumor from normal cells. Epithelial growth factor receptor (EGFR) plays a critical role in oncogenesis across several cancers and is often upregulated. 1 While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin and gastrointestinal toxicity, which constrains dose escalation and efficacy.2 A2B395 is an allogeneic, logic-gated, EGFR-targeted, Tmod CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR and a blocker targeting human leukocyte antigen (HLA)-A*02. The activator recognizes EGFR on both tumor and normal cells, whereas the blocker inhibits CAR T activity against normal cells with preserved HLA expression, decreasing the risk for graft-vs-host disease (ie, on-target, off-tumor toxicity).3 To address potential graft-vs-host response, a short-hairpin RNA expression module targeting beta-2 microglobulin is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response.4 Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy sug...