Genetically Engineered Immune Cell and Polypeptide Systems for Precision Combinatorial Targeting of Cancer Cells

Background

Cancer immunotherapy is a rapidly evolving field that seeks to harness the body’s own immune system to recognize and destroy malignant cells. Among the most promising approaches are adoptive cell therapies, such as chimeric antigen receptor (CAR) T cell therapy, which involve engineering a patient’s immune cells to target specific markers on cancer cells. The rationale for these therapies is rooted in the observation that cancer cells often express unique or overexpressed antigens not found, or found at much lower levels, on normal tissues. However, the heterogeneity of tumor antigen expression and the similarity of some tumor markers to those on healthy cells present significant challenges. There is a critical need for technologies that can increase the precision of immune cell targeting to maximize tumor destruction while minimizing collateral damage to normal tissues.

Current immunotherapeutic strategies, particularly those relying on single-antigen targeting, face substantial limitations. Many tumor-associated antigens are not exclusively expressed on cancer cells, leading to the risk of on-target, off-tumor toxicity—where healthy tissues expressing the target antigen are also attacked, resulting in severe and sometimes fatal side effects. Furthermore, tumors can evade immune detection by downregulating or losing the targeted antigen, leading to relapse. Existing approaches lack the ability to integrate complex antigenic information, making it difficult to distinguish cancer cells from normal cells that share some, but not all, surface markers. As a result, there is a pressing need for more sophisticated targeting strategies that can improve specificity and safety by recognizing unique combinations of antigens rather than relying on single markers.

Technology

This technology centers on the use of genetically engineered immune cells—such as T cells or natural killer (NK) cells—that are programmed to recognize and respond to specific combinations of cell surface antigens found on cancer cells. By incorporating multiple antigen-triggered polypeptides, these cells implement Boolean logic gates (AND, AND-NOT, OR) at the molecular level, enabling precise discrimination between cancerous and healthy tissues. Key components include chimeric antigen receptors (CARs) for immune activation, inhibitory CARs (iCARs) to suppress responses to healthy tissue markers, and synthetic receptors like synNotch that act as binding-triggered transcriptional switches, controlling the expression of secondary effectors. The system also features polyspecific immune-inducing polypeptides (PIIPs) that can bind multiple antigens simultaneously, and leverages advanced bioinformatic pipelines to select optimal antigen pairs for each cancer type. The approach encompasses both cell-based therapies—where patient immune cells are engineered and reinfused—and direct administration of multi-specific antibodies.

What differentiates this technology is its modular, programmable design that dramatically enhances the specificity and safety of cancer immunotherapy. Unlike conventional therapies that target single antigens and risk damaging healthy tissues with similar markers, this solution uses combinatorial antigen recognition, requiring unique patterns of antigen expression for immune activation. The integration of Boolean logic gates allows for highly customizable targeting strategies, including activation only in the presence of cancer-specific antigen combinations or suppression when healthy tissue markers are detected. The use of bioinformatic analysis ensures that antigen pairs are chosen for maximal discrimination, reducing off-target effects. Additionally, the platform’s flexibility—accommodating both engineered immune cells and multi-specific antibodies—broadens its applicability across a wide range of cancers. Extensive experimental validation and a comprehensive antigen pair library further support its clinical potential, positioning this technology as a significant advancement in precision cancer therapy.

Benefits

• Enhanced specificity in targeting cancer cells through combinatorial antigen recognition, reducing off-target effects on healthy tissues.
• Implementation of Boolean logic gates (AND, AND-NOT, OR) in immune cells for precise discrimination based on multiple antigen expression patterns.
• Use of diverse antigen-triggered polypeptides, including CARs, inhibitory CARs (iCARs), and synthetic receptors like synNotch, enabling modular and programmable immune activation.
• Data-driven selection and validation of optimal antigen pairs for various cancer types using bioinformatic analysis of gene and protein expression.
• Versatile therapeutic modalities including genetically engineered immune cells and polyspecific immune-inducing polypeptides (PIIPs) such as bispecific or trispecific antibodies.
• Methods for ex vivo genetic modification and expansion of patient immune cells, facilitating personalized and targeted cancer immunotherapy.
• Extensive experimental validation demonstrating improved efficacy and safety of combinatorial antigen targeting strategies.

Applications

• Personalized cancer cell immunotherapy
• Bispecific/trispecific antibody therapeutics
• Precision solid tumor targeting
• Minimizing off-tumor toxicities
• Bioinformatic antigen pair discovery

Additional info

This platform employs genetically engineered immune cells programmed with Boolean logic gates—AND, AND-NOT, and OR—to recognize combinatorial antigen patterns. Utilizing chimeric antigen receptors, inhibitory CARs, and synNotch transcriptional switches, the system distinguishes malignant from healthy tissues. Supported by bioinformatic antigen pair selection, these cytotoxic cells or polyspecific polypeptides enhance therapeutic precision, minimizing off-target toxicity by requiring specific multi-antigen signatures for activation.