A2 Bio Advances Logic-Gated CAR-T Therapy A2B543 in EVEREST-2 Trial for Solid Tumors

Agoura Hills, Calif., February 26, 2026 –

A2 Biotherapeutics, Inc. (A2 Bio) announced that the first patient has been dosed with A2B543, initiating the second arm of the Phase 1/2 EVEREST-2 clinical study (NCT06051695). The milestone represents an important step forward for the company’s Tmod™ platform, a next-generation immunotherapy approach designed to selectively eliminate tumor cells while sparing healthy tissue.

A2B543 is an autologous CAR-T cell therapy engineered using A2 Bio’s proprietary Tmod™ logic-gated technology, which enables highly selective targeting of cancer cells. The therapy builds on earlier Tmod™ constructs by incorporating an inducible, membrane-tethered IL-12 booster, a cytokine designed to strengthen the anti-tumor activity of CAR-T cells within the tumor microenvironment. Unlike systemic IL-12 therapies, which have historically been limited by severe toxicity, the inducible membrane-bound IL-12 in A2B543 is activated only when Tmod™ cells engage tumor antigens. This localized activation aims to enhance CAR-T persistence and potency while minimizing systemic adverse effects.

According to A2 Bio leadership, the first patient dosing marks a major advancement for the platform’s clinical development. “Dosing the first patient with A2B543 is a significant step forward in the evolution of the Tmod™ platform,” said John Welch, M.D., Ph.D., Chief Medical Officer of A2 Bio. Welch explained that while IL-12 is known to drive strong anti-tumor immune responses, its clinical use has been constrained by toxicity when delivered systemically. By engineering an inducible membrane-tethered IL-12 component into the CAR-T cells, the company aims to concentrate the cytokine’s activity directly within the tumor microenvironment, improving therapeutic potency without triggering widespread immune toxicity.

A2B543 is being evaluated as part of the EVEREST-2 master protocol, a seamless Phase 1/2 clinical study assessing investigational therapies developed from the Tmod™ platform. The trial evaluates two autologous cell therapies: A2B694, which forms the first study arm, and A2B543, which incorporates the additional IL-12 booster element. Both therapies use the Tmod™ dual-receptor system that combines a tumor-targeting activator receptor with a protective blocker receptor. The activator recognizes mesothelin (MSLN), a tumor-associated antigen frequently expressed in multiple solid tumors, while the blocker targets HLA-A*02, a molecule typically present on normal cells but often lost in tumor cells through a process known as loss of heterozygosity (LOH). This design enables the engineered cells to distinguish between malignant and healthy tissue, allowing tumor cells to be destroyed while normal cells remain protected.

The EVEREST-2 study is enrolling adult patients with germline heterozygous HLA-A*02 who have recurrent, unresectable, locally advanced, or metastatic solid tumors that express mesothelin and have lost HLA-A*02 expression. Targeted cancer indications include colorectal cancer, pancreatic cancer, non-small cell lung cancer, ovarian cancer, mesothelioma, and other mesothelin-positive tumors.

Patient identification for EVEREST-2 is facilitated through BASECAMP-1 (NCT04981119), a master prescreening study designed to efficiently identify eligible candidates for A2 Bio’s precision medicine trials. BASECAMP-1 uses next-generation sequencing to detect HLA loss of heterozygosity in patients at any stage of their disease. Once enrolled in BASECAMP-1, patients who experience disease progression may be directly screened for participation in EVEREST-2 without a mandatory waiting period between studies. The prescreening platform integrates AI-enabled precision diagnostics, helping researchers rapidly identify suitable candidates while reducing the time and cost associated with clinical trial recruitment.

Beyond A2B543 and A2B694, A2 Bio’s pipeline includes additional investigational programs such as A2B395, along with several preclinical candidates designed to expand the company’s portfolio of logic-gated therapies. The Tmod™ platform itself represents a flexible technology suite capable of generating both autologous and allogeneic cell therapies, with potential applications across multiple cancers and other serious diseases.

The dosing of the first patient with A2B543 marks a significant milestone not only for A2 Bio but also for the broader field of precision-engineered cell therapies for solid tumors. By combining tumor-specific logic gating with inducible cytokine enhancement, the therapy seeks to address two major challenges that have historically limited CAR-T success in solid cancers: tumor specificity and persistence within the immunosuppressive tumor microenvironment.

As the EVEREST-2 trial progresses, researchers will evaluate the safety, tolerability, and early efficacy signals of A2B543, helping determine whether this next-generation CAR-T design can deliver improved outcomes for patients with difficult-to-treat solid tumors.