Work

559 Armoring logic-gated CAR T cells with a membrane-tethered IL-12 booster: initial data from the EVEREST-2 study of A2B543 in advanced solid tumors

Year: 2026

Type: conference-paper

Abstract: Background A2B543 is an autologous, logic-gated Tmod TM chimeric antigen receptor T-cell (CAR T) therapy that contains a mesothelin (MSLN) CAR activator, an HLA-A*02 blocker, and is armored with a membrane-tethered interleukin-12 (IL-12) booster (figure 1). The logic-gated design enables selective targeting of tumor versus normal cells to improve the safety and efficacy of MSLN-targeted therapies.1 2 The membrane-tethered IL-12 booster is designed to enhance persistence and potency while avoiding systemic IL-12 toxicity that could occur if IL-12 were to be secreted or shed.3 4 A2B694 is comprised of the identical Tmod CAR T construct without the membrane-tethered IL-12 booster.5Methods EVEREST-2 ( NCT06051695) is an open-label, Phase 1/2 dose-finding study of A2B543 and A2B694 in adults with previously treated MSLN+ advanced solid tumors. The prescreening study BASECAMP-1 (NCT04981119) identifies eligible patients with germline HLA-A*02 heterozygosity and tumor-associated HLA-A*02 loss of heterozygosity (LOH).Results As of 21 May 2026, 2 patients were treated with the A2B543 IL-12 booster therapy at dose level 4×10 8 cells. Both patients were 45-year-old women with pancreatic cancer (1 Asian, 1 non-Hispanic White). The first patient completed the 21-day safety review period. Thirteen patients were treated with A2B694: 8 women, 5 men; median age 59; tumor types included colorectal (n = 4), ovarian (n = 3), pancreatic (n = 3), non–small cell lung adenocarcinoma (NSCLC), gastro-esophageal, and mesothelioma (n = 1 each); dose levels ranged from 1 × 108 to 6 × 108 cells.Across both cohorts, lymphodepletion prior to Tmod CAR T administration was well-tolerated, with expected, transient cytopenias. There were no dose-limiting toxicities, new safety signals, or grade 3/4 adverse events related to Tmod CAR T reported. In the A2B694 cohort, 1 patient had grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) and 1 patient had grade 1 cytokine release syndrome (CRS).The first patient receiving A2B543 and all patients who received A2B694 were efficacy-evaluable and had Tmod blocker detected post-infusion in peripheral blood. The patient who received A2B543 demonstrated higher expansion than 12 of the 13 patients who received A2B694 (figure 2). One patient with KRASG12V/STK11-mutated NSCLC who received A2B694 achieved a complete response (CR) at D90 per RECIST 1.1 by central review; the patient continued to do well at 12 months post-CAR-T transfusion.Conclusions A2B543 and A2B694 demonstrated manageable safety and tolerability in patients with advanced MSLN-expressing solid tumors with tumor-associated HLA-A*02 LOH. The incorporation of the membrane-tethered IL-12 booster in A2B543 enhanced expansion. Dose-escalation continues, as the maximum tolerated dose has not been reached.Acknowledgements The authors thank the patients, their families, and their caregivers for participating in this trial; the screeners, clinical research coordinators, study nurses, data managers, and apheresisteams at each study site; and 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.Jia Z, et al. IL12 immune therapy clinical trial review: Novel strategies for avoiding CRS-associated cytokines. Front Immunol. 2022;13:952231.Zhang JA, et al. Onboard, tethered IL-12 boosts potency of the Tmod NOT gate and preserves selectivity. J Immunother Cancer. 2025;13(5):e010976.Hamburger AE, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310.Ethics Approval This trial was approved by each site’s institutional review board.Abstract 559 Figure 1Membrane-tethered, IL-12-boosted, logic-gated CAR T therapy designed to reduce toxicity: MSLN (activator in blue) and HLA-A*02 (blocker in red)Abstract 559 Figure 2Tmod blocker detected in the peripheral blood of all patients

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0559