Fourth-Generation Dual CAR-T Cells Targeting Nectin-4 and FAP

The Dual‑Target Fourth‑Generation CAR‑T platform is an advanced armored CAR‑T cell therapy specifically engineered to address the biological and immunological barriers of solid tumors. By simultaneously targeting tumor cells and the tumor microenvironment, this approach aims to improve tumor infiltration, persistence, and overall antitumor efficacy.

Dual-Target Design for Synergistic Benefits

Nectin‑4 is a tumor‑associated antigen highly expressed in multiple solid tumors, including bladder cancer, breast cancer, lung cancer, and pancreatic cancer. Targeting Nectin‑4 enables direct recognition and elimination of malignant tumor cells.

Fibroblast activation protein (FAP) is selectively expressed on cancer‑associated fibroblasts (CAFs), a key structural and immunosuppressive component of the tumor stroma. Targeting FAP disrupts the tumor microenvironment and facilitates CAR‑T cell penetration.

The dual‑target strategy is designed to reduce antigen escape and overcome physical and immunological barriers that limit the effectiveness of conventional CAR‑T therapies in solid tumors.

The Fourth-Generation CAR-T with Functional Enhancements

The fourth-generation CAR-T therapy incorporates inducible cytokine expression modules, such as IL-7/CCL19 or IL-12, to further enhance therapeutic performance:

• Promote CAR-T cell survival and long-term persistence
• Recruit endogenous immune cells to the tumor site
• Remodel the tumor microenvironment from immunosuppressive to immunoactive

Therapeutic Principles

The therapeutic principles of the fourth-generation CAR-T cell therapy targeting Nectin-4 and FAP are based on a multi-dimensional approach to tumor eradication:

• Direct Tumor Cell Elimination: CAR-T cells recognize and kill tumor cells expressing Nectin-4.
• Tumor Microenvironment Disruption: By targeting FAP, CAR-T cells break down stromal barriers, reduce immunosuppression, and improve immune cell access.
• Immune Recruitment and Modulation: Cytokine armoring with IL-7/CCL19 or IL-12 can recruit endogenous immune cells and enhances CAR-T persistence and functionality within the tumor.
• Antigen Escape Prevention: Dual-target recognition reduces the likelihood of tumor cells evading immune detection.

Key Advantages

• Dual-target recognition addresses both tumor cells and the supportive stroma.
• Enhanced tumor infiltration due to microenvironment modulation.
• Cytokine armoring prolongs CAR-T cell persistence and recruits additional immune cells.
• Reduced risk of tumor escape through simultaneous targeting of multiple antigens.
• Tailored for solid tumors, overcoming challenges not addressed by conventional CAR-T therapies.

Potential Therapeutic Indications

Accumulating clinical and translational studies indicate that Nectin-4 is highly expressed in multiple epithelial malignancies, supporting its potential as a therapeutic target across the following cancer types.

• Fourth-Generation Nectin4/FAP-Targeted CAR-T for Malignant Solid Tumors