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Background Mesothelin (MSLN) is overexpressed in many cancer types. Loss of heterozygosity (LOH) may provide a means to target tumor versus normal cells 1 and to augment the efficacy and safety of MSLN-targeted programs2–4. A2B694 is an autologous, logic-gated, Tmod CAR T therapy to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR T activator with a human leukocyte antigen (HLA)-A*02 blocker (figure 1)5 6.Methods The first-in-human, open-label, phase 1/2 EVEREST-2 study is evaluating safety and efficacy of A2B694 in patients with recurrent/metastatic MSLN-expressing cancers with tumor-associated HLA-A*02 LOH. The prescreening study BASECAMP-1 ( NCT04981119) identifies eligible patients and cryopreserves leukapheresis product. Upon progression, A2B694 is manufactured and administered after lymphodepletion. Phase 1 primary objective: evaluate the safety and tolerability of A2B694 and identify a recommended phase 2 dose (RP2D). Phase 2 primary objective: assess overall response rate.Results As of May 23, 2025, 7 patients were enrolled: 5 women/2 men, median age 59y, 6 non-Hispanic White/1 Hispanic with unknown race. Tumor types included ovarian (n=3), pancreatic (n=2), non-small cell lung adenocarcinoma (NSCLC; n=1), and colorectal (n=1). A2B694 dose groups were 1×10 8 (n=3) and 2×108 (n=4) cells. Lymphodepletion was well-tolerated, with expected, transient cytopenias. All patients had ≥1 adverse event, most commonly chest pain (non-cardiac), fatigue, and neutropenia (each in 4 patients) and anemia, cough, decreased appetite (1 serious), leukopenia, and lymphopenia (each in 3 patients). One patient had Grade 3 ICANS and was treated with a prolonged course (41 days) of dexamethasone. There were no dose-limiting toxicities, cytokine release syndrome, or new safety signals after 9 months of follow-up.All 7 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood and in a tumor biopsy collected on Day (D) 42, demonstrating that A2B694 persists in the tumor microenvironment (figure 2). Six patients had progressive disease by D90. The patient with KRASG12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion and had a confirmed CR per RECIST 1.1 by central review at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease.Conclusions A2B694 has manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. CR per RECIST 1.1 was observed in 1 patient with KRAS G12V/STK11 co-mutated NSCLC. The maximum tolerated dose has not been reached and the dose-escalation phase to determine the RP2D continues.Acknowledgements The authors would like to thank the patients, their families, and their caregivers for participating in this trial; the screeners, clinical research coordinators, study nurses, data managers, and apheresis teams at each study site; and A2 Bio. Medical writing support was provided by Jennifer M. Kulak, PhD, of ApotheCom (Yardley, PA) and funded by A2 Bio.Trial Registration ClinicalTrials.gov, NCT06051695References Hecht J, et al. Next generation sequencing (NGS) to identify relapsed gastrointestinal (GI) solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for future logic-gated CAR T therapy to reduce on target off tumor toxicity. J Clin Oncol. 2022;40(suppl 4):190.Beatty GL, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology. 2018;155:29–32.Haas AR, et al. Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells. Mol Ther. 2023;31:2309–2325.Hong D, et al. 959O Gavocabtagene autoleucel (gavo-cel, TC-210) dose escalation in refractory mesothelin-expressing solid tumors. Ann Oncol. 2021;32(suppl 5):S830.Hamburger AE, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310.Punekar SR, et al. EVEREST-2: Initial data of the logic-gated Tmod chimeric antigen receptor T-cell (CAR T) therapy A2B694 for patients with solid tumors associated with mesothelin (MSLN) expression and with human leukocyte antigen (HLA) loss of heterozygosity (LOH). J Clin Oncol. 2025;43(16 suppl):3040.Ethics Approval This trial was approved by each site’s institutional review board.Abstract 535 Figure 1The structure of Tmod CAR T cells expressing a MSLN-targeted activator and an HAL-A*02-targeted blockerAbstract 535 Figure 2A2B694 levels over time