Ward, Jeffrey

TPS2673 Background: The main challenge for developing CAR T therapies for solid tumors is the lack of targets that distinguish tumor from normal cells, resulting in on-target, off-tumor toxicity. Tmod logic-gated CAR T therapy addresses this challenge by incorporating 2 CARs on the same T cell: an activator targeting a marker on both tumor and normal cells, and a blocker targeting HLA-A*02 that inhibits CAR T activity against normal cells while allowing activation against tumor cells (with HLA-A*02 LOH), improving tumor selectivity and decreasing toxicity. Early safety results from 3 ongoing phase 1/2 clinical trials of logic-gated, Tmod CAR T therapy (EVEREST-1, EVEREST-2, and DENALI-1) have demonstrated manageable safety and tolerability in patients with advanced solid tumors (Grierson et al, SITC , 2024; Ward et al, SITC 2025; Specht et al, SABCS , 2025). Early efficacy results include the first ever reported complete response in a patient with non-small cell lung cancer following treatment with a CAR T-cell therapy (A2B694). A2B543 is an autologous Tmod CAR T therapy that contains the same Tmod construct as A2B694 with an added membrane-tethered IL-12 (memIL12) booster. Specifically, A2B543 is comprised of autologous Tmod cells transduced with 2 lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the mesothelin-targeted CAR activator; and a second expressing the memIL12 booster. Interleukin 12 (IL-12) is a potent, pro-inflammatory cytokine that plays a crucial role in inducing antitumor immune responses; however, systemic IL-12 can be prohibitively toxic (Jia et al, Front Immunol , 2022). In A2B543, expression of the memIL12 cassette is under the control of an NFAT promoter and is induced during antigen engagement or T cell activation. This inducible memIL12 is designed to reduce the toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod (Zhang et al, J Immunother Cancer , 2025). Methods: EVEREST-2 (NCT06051695) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B543 in adults with recurrent/metastatic mesothelin-expressing cancers with tumor-associated HLA-A*02 LOH, including mesothelioma, colorectal, non-small cell lung, pancreatic, or ovarian cancer. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH via next-generation sequencing and cryopreserves leukapheresis product. Upon progression, A2B543 is manufactured and then administered after lymphodepletion. The phase 1 primary objective is to evaluate the safety and tolerability of A2B543 and identify a recommended phase 2 dose (RP2D). The phase 2 primary objective is to assess overall response rate. Clinical trial information: NCT06051695 .

8579 Background: LOH may provide a means to target tumor versus normal cells, to augment the efficacy and safety of MSLN-targeted programs (Hecht et al. JCO . 2022). A2B694 is an autologous, logic-gated, Tmod CAR T therapy designed to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR activator with an HLA-A*02 blocker (Hamburger et al. Mol Imm. 2020). Methods: The first-in-human, open-label, phase 1/2 EVEREST-2 (NCT06051695) study 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. Results: As of 05 January 2026, 13 patients were enrolled: 8 women/5 men, median age 59 years, 11 non-Hispanic White/2 Hispanic with unknown race. 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). A2B694 dose level (DL) groups were: DL1: 1×10 8 cells (n = 3), DL2: 2×10 8 cells (n = 4), DL3: 4×10 8 cells (n = 5), and DL4: 6×10 8 cells plus low-dose IL-2 (n = 1). Lymphodepletion prior to administration of A2B694 was well-tolerated, with expected, transient cytopenias. The only adverse event reported in more than 1 patient was grade 3 neutropenia. One patient had grade 3 ICANS and 1 patient had grade 1 CRS. There were no dose-limiting toxicities or new safety signals after up to 17 months follow-up. All 13 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood. While A2B694 was not detected in tumor biopsies collected in patients treated at DL1 (0/2), all patients treated at DL2-DL4 with available biopsies (3/3) had detectable A2B694 in the tumor microenvironment. A patient with KRAS G12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion per RECIST 1.1 by central review and had a confirmed CR at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease. On D243, the patient had a CNS relapse, with an ongoing non-CNS CR per RANO-BM at D284. At M12, the patient's CT showed no new findings and persistence of A2B694 in the blood was confirmed by ddPCR. Conclusions: We report the first patient with NSCLC to have a CR after CAR T. Overall, A2B694 demonstrated manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. The maximum tolerated dose has not been reached; dose-escalation continues. Clinical trial information: NCT06051695 .