Novel Dual-Receptor CAR T-Cell Therapy A2B694 Enters Clinical Trial for Pancreatic Cancer Treatment

Key Insights

• A novel CAR T-cell therapy A2B694, featuring both activating and inhibitory receptors, enters Phase 1/2 EVEREST-2 trial for mesothelin-expressing solid tumors, including pancreatic cancer.
• The therapy's unique dual-receptor design aims to overcome previous limitations of mesothelin-targeted CAR T-cell treatments by reducing on-target, off-tumor toxicity.
• Patient selection focuses on individuals with HLA-A*02 heterozygosity and tumor loss of heterozygosity, enabling selective targeting of cancer cells while protecting normal tissues.

A groundbreaking CAR T-cell therapy with a novel dual-receptor design is advancing into clinical trials, offering new hope for patients with pancreatic cancer and other mesothelin-expressing solid tumors. The Phase 1/2 EVEREST-2 trial (NCT06051695) is now evaluating A2B694, a CAR T-cell product engineered with both activating and inhibitory receptors.

Dr. Kristen Spencer, associate professor at NYU Grossman School of Medicine and director of the Phase 1 Developmental Therapeutics Program at NYU Langone Perlmutter Cancer Center, explains the innovative approach: "We've seen CAR T constructs directed against mesothelin in the past, but they were really limited by on-target, off-tumor toxicity. A2B694 is a novel CAR T product that has both an activating and an inhibitory receptor."

Innovative Dual-Receptor Mechanism

The therapy's distinctive design addresses a critical challenge in CAR T-cell treatment of solid tumors. The activating receptor targets mesothelin, a protein expressed in both tumor and normal cells, while the inhibitory receptor recognizes HLA-A*02. This dual-receptor system creates a sophisticated mechanism for selective tumor targeting.

Strategic Patient Selection

Patient selection plays a crucial role in the trial's approach. Eligible participants must have recurrent, unresectable, locally advanced, or metastatic cancers with mesothelin expression. The BASECAMP-1 study (NCT04981119) serves as a prescreening platform, using next-generation sequencing to identify patients with tumor-associated HLA-A*02.

Protection of Healthy Tissue

The therapy's protective mechanism relies on patients being heterozygous for HLA-A*02 in their germline, with loss of heterozygosity for that allele in the tumor. Dr. Spencer elaborates: "When this occurs, it protects the normal cells as they engage the inhibitor receptor, which helps destroy tumor cells because they aren't able to recognize what the inhibitor receptor does."

Trial Scope and Potential Impact

The open-label, nonrandomized EVEREST-2 trial encompasses multiple solid tumor types, including pancreatic cancer and colon cancer. This broad approach could potentially address the significant unmet need in treating mesothelin-expressing solid tumors, which have historically proven resistant to CAR T-cell therapy due to toxicity concerns.