Abstract A126: Armoring logic-gated CAR T cells with a membrane-tethered IL-12 booster: initial data from the EVEREST-2 study of A2B543 in patients with advanced pancreatic cancer
Salman R. Punekar, Jeffrey P. Ward, Monica Avila, Patrick M. Grierson, Kedar Kirtane, Jennifer M. Specht, David B. Zhen, Frederick L. Locke, David G. Maloney, Sandip P. Patel, Oliver Dorigo, Marcela V. Maus, Marco Davila, Cathy Eng, Antonious Hazim, Jasmine Mitchell, Zachary P. Yeung, Yanyan Lou, Jinesh S. Gheeya, Matthew Ulrickson, Theodore Welling, Peter Vu, Gregory Botta, Kristen K. Ciombor, Ryan M. Carr, Constance Fiocco, Armen Mardiros, Jackie D. Xuan, Eric W. Ng, John S. Welch, Julian R. Molina, Joel R. HechtAbstract
Background:
A2B543 is an autologous, logic-gated TmodTM 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. The logic-gated design enables selective targeting of tumor versus normal cells to improve the safety and efficacy of MSLN-targeted therapies. 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. A2B694 is comprised of the identical Tmod CAR T construct (MSLN activator with HLA-A*02 blocker) without the membrane-tethered IL-12 booster.
Methods:
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.
Results:
As of 15 June 2026, 2 patients with pancreatic cancer were treated with the IL-12 boosted Tmod CAR T therapy A2B543 at dose level 1 (4×108 cells). Both patients were 45-year-old women (1 Asian, 1 non-Hispanic White) and completed the 21-day safety review period. Thirteen patients were treated with A2B694 (absent the IL-12 booster): 8 women, 5 men; median age 59; tumor types included colorectal (CRC) (n=4), pancreatic (n=3), ovarian (n=3), non-small cell lung adenocarcinoma, 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, and no grade 3/4 adverse events related to Tmod CAR T. In the A2B543 cohort, 1 patient had grade 1 cytokine release syndrome (CRS). In the A2B694 cohort, 1 patient with pancreatic cancer had grade 3 ICANS and 1 patient with CRC had both grade 1 ICANS and grade 1 CRS. All patients had Tmod blocker detected by ddPCR post-infusion in peripheral blood. The two A2B543 patients demonstrated higher peak expansion and area under the curve than 12 of the 13 A2B694 patients. Serum IL-12 concentrations did not exceed 5 pg/ml in the two A2B543 patients through Day 56 and Day 14, respectively.
Conclusions:
A2B543 and A2B694 demonstrated manageable safety and tolerability in patients with advanced MSLN-expressing solid tumors with tumor-associated HLA-A*02 loss of heterozygosity. The incorporation of the membrane-tethered IL-12 booster in A2B543 enhanced expansion compared to A2B694, and maintained a tolerable safety profile, highlighting early promise for pancreatic cancer applications. Dose-escalation continues, as the maximum tolerated dose has not been reached.
Citation Format:
Salman R. Punekar, Jeffrey P. Ward, Monica Avila, Patrick M. Grierson, Kedar Kirtane, Jennifer M. Specht, David B. Zhen, Frederick L. Locke, David G. Maloney, Sandip P. Patel, Oliver Dorigo, Marcela V. Maus, Marco Davila, Cathy Eng, Antonious Hazim, Jasmine Mitchell, Zachary P. Yeung, Yanyan Lou, Jinesh S. Gheeya, Matthew Ulrickson, Theodore Welling, Peter Vu, Gregory Botta, Kristen K. Ciombor, Ryan M. Carr, Constance Fiocco, Armen Mardiros, Jackie D. Xuan, Eric W. Ng, John S. Welch, Julian R. Molina, Joel R. Hecht. Armoring logic-gated CAR T cells with a membrane-tethered IL-12 booster: initial data from the EVEREST-2 study of A2B543 in patients with advanced pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A126.