Boosted CAR Compositions for Solid Tumor Penetration and Persistence
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current chimeric antigen receptor (CAR) therapies face challenges in treating solid tumors due to tumor antigen escape, insufficient persistence of engineered CAR molecules, reduced effectiveness in the solid tumor environment, and safety issues such as cytokine release syndrome and immune toxicity, limiting their clinical application.
Innovation Solution
Development of boosted CAR compositions with high surface expression, multi-targeting capabilities, armor elements to overcome immunosuppression, cytokine-stimulated elements for enhanced anti-tumor cytotoxicity, digestive enzymes for tumor penetration, and on/off switches for controlled expression, encoded in a single multi-cistronic vector for improved therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR therapies are used to treat solid tumors, then tumor targeting capability is achieved, but tumor penetration and persistence are insufficient
Solution Approach 1:
The patent applies composite materials by creating a multi-component CAR structure that combines multiple functional elements: antigen-binding domains (scFv), costimulatory domains (CD28, 4-1BB), cytokine domains (IL-7, IL-15), and tumor-penetrating peptides. This composite CAR design enhances both tumor targeting reliability and persistence by integrating multiple functions into a single engineered receptor that can simultaneously bind antigens, receive costimulatory signals, secrete cytokines for local immunostimulation, and penetrate tumor microenvironment barriers.
Solution Approach 2:
The patent employs the nested doll principle by placing multiple functional domains within a hierarchical CAR structure. The antigen-binding scFv domain is nested within the extracellular region, costimulatory domains are nested in the transmembrane region, and cytokine domains are nested in the intracellular region. This nested arrangement allows each functional element to operate independently while contributing to the overall persistence and effectiveness of the CAR therapy in solid tumors.
2Reliability
If CAR therapies are used to treat solid tumors, then antigen binding is achieved, but tumor penetration through stroma is reduced
Solution Approach 1:
The patent uses the intermediary principle by incorporating tumor-penetrating peptides (such as penetratin, TAT, or cell-penetrating peptides) as mediators that facilitate CAR T-cell infiltration through the tumor stroma. These peptides act as intermediaries between the CAR T-cells and the dense extracellular matrix, enabling the T-cells to navigate through physical barriers while maintaining their antigen-binding capability. The intermediary peptides temporarily interact with stromal components to enable penetration without permanently altering the CAR structure.
3Power
If CAR therapies are used to treat solid tumors, then cytotoxic activity is achieved, but safety issues such as cytokine release syndrome and immune toxicity occur
Solution Approach 1:
The patent applies local quality by engineering the CAR to secrete cytokines (IL-7, IL-15) locally at the tumor site rather than systemically. This localized cytokine secretion creates a concentrated immunostimulatory microenvironment directly at the tumor, enhancing cytotoxic activity where needed while minimizing systemic cytokine release and associated toxicities. The local quality principle ensures that the harmful effects are confined to the treatment site while the beneficial effects are amplified locally.
Solution Approach 2:
The patent employs self-service by designing the CAR to autonomously regulate its own activity through built-in checkpoint mechanisms and controlled cytokine secretion. The engineered CAR can sense tumor microenvironment conditions and self-adjust its cytotoxic activity and cytokine release accordingly, reducing the risk of uncontrolled immune activation and toxicity while maintaining effective anti-tumor responses. This self-regulating capability allows the therapy to serve itself in managing safety without requiring external intervention.
4Ease of manufacture
If single-targeting CARs are used, then manufacturing simplicity is maintained, but tumor antigen escape occurs
Solution Approach 1:
The patent applies universality by creating a multi-targeting CAR that can recognize and bind to multiple different tumor antigens simultaneously or sequentially. The engineered CAR incorporates multiple antigen-binding domains targeting different antigens (such as HER2, ROR1, MSLN, or other solid tumor-associated antigens), allowing a single CAR construct to provide universal coverage against heterogeneous tumor populations. This multi-functionality prevents antigen escape by ensuring that tumor cells cannot evade therapy by downregulating a single antigen while maintaining manufacturing feasibility through a unified CAR design.
Data Source
AI summary
Novel anti-effector moiety antibodies or antigen binding domains thereof and CARs that contain such effector moiety antigen binding domains, either with or without one or more booster elements, and host cells expressing the receptors, and nucleic acid molecules encoding the receptors are provided herein, as well as methods of use of same in a patient-specific immunotherapy that can be used to treat solid tumor cancers and other diseases and conditions.