BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies1; however, implementation of these therapies in solid tumors has been challenging due to a lack of tumor-specific targets that discriminate cancer from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and T-cell engagers have resulted in dose-limiting, on-target, off-tumor toxicities.2 3 EVEREST-1 (NCT05736731) is a seamless, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B530, a logic-gated CEA-targeting Tmod CAR T-cell therapy, in adult patients. Tmod CAR T-cell therapy addresses challenges of on-target, off-tumor toxicity by combining a CAR-activating receptor with a blocking receptor to discriminate tumor from normal cells (figure 1).4 5 The activator receptor recognizes CEA on the surface of both tumor and normal cells. CEA is normally widely expressed in epithelial cells, particularly of the gastrointestinal (GI) system and can be upregulated in GI and lung tumors. Specificity for tumor cells is provided by a blocker that recognizes human leukocyte antigen (HLA) A*02, which is absent on tumor cells with HLA-A*02 LOH.6 LOH for HLA-A*02 is observed in solid tumor malignancies and can be detected using the Tempus next-generation sequencing testing. With this definitive discriminator target, A2B530 can potentially provide a therapeutic window to treat patients with CEA-expressing solid tumors exhibiting HLA LOH.MethodsPatients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease. BASECAMP-1 eligible patients undergo leukapheresis and, when clinically appropriate, their banked T cells are manufactured for the EVEREST-1 study (figure 2). The key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers that are associated with CEA expression: non-small cell lung (NSCLC), colorectal (CRC), or pancreatic (PANC) cancers. Patients should have received ≥1 line of prior therapy (eg, checkpoint inhibitor, molecular-targeted, or chemotherapy). The primary objective of phase 1 is to evaluate the safety and tolerability of A2B530 in patients with NSCLC, CRC, and PANC, and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B530.Trial RegistrationNCT05736731References1. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640–654.2. Parkhurst MR, Yang JC, Langan RC, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19:620–626.3. Tabernero JT, Melero I, Ros W, et al. Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 2017;35(15_Suppl):3002.4. Hamburger AE, DiAndreth B, Cui J, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310.5. DiAndreth B, Hamburger A, Xu H, Kamb A. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022;241:109030.6. Sandberg ML, Wang X, Martin AD, et al. A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo. Sci Transl Med. 2022;14:eabm0306.Ethics ApprovalThis study was approved by site IRBs.Abstract 634 Figure 1CEA CAR Tmod Single Vector ConstructAbstract 634 Figure 2Everest-1 Study Design