TIM-1 Targeting CARs for Solid Tumor Killing
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Solution Overview
Problem
Current chimeric antigen receptor (CAR) T cell therapy has limited success in treating solid tumors due to immunosuppressive tumor microenvironments, reduced tumor sensitivity, and lack of tumor-selective targeting, which contrasts with its effectiveness in hematological malignancies.
Innovation Solution
Development of CARs targeting T cell immunoglobulin and mucin domain 1 (TIM-1) protein, comprising an antigen-binding domain, a transmembrane domain, and intracellular signaling domains, specifically designed to bind to TIM-1 and activate immune cells for targeted killing of TIM-1-expressing cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cell therapy is applied to solid tumors, then immune cells can target tumor cells, but the immunosuppressive tumor microenvironment reduces therapy effectiveness
Solution Approach 1:
The patent introduces TIM-1 as a specific intermediary target on tumor cells that CAR T cells can recognize and bind to. This mediator enables selective targeting of tumor cells while avoiding the suppressive effects of the tumor microenvironment, as TIM-1 is preferentially expressed on tumor cells rather than healthy cells in the microenvironment.
Solution Approach 2:
The patent applies local quality by making the CAR T cells selectively responsive only when TIM-1 is present on tumor cell surfaces. The CAR construct is designed with specific antigen-binding domains that recognize TIM-1, creating a localized activation response only at tumor sites where TIM-1 is expressed, while remaining inactive in the broader immunosuppressive microenvironment.
2Reliability
If CAR T cell therapy is used for solid tumors, then tumor cells can be targeted, but tumor sensitivity to T cell-mediated killing is reduced
Solution Approach 1:
TIM-1 serves as a reliable intermediary marker that is consistently expressed on solid tumor cells including ovarian clear cell carcinoma and renal cell carcinoma. The CAR T cells use TIM-1 binding as an intermediary step to deliver cytotoxic effects, bypassing the reduced sensitivity issues associated with direct T cell recognition of solid tumor antigens.
3Reliability
If traditional CAR T cell therapy is applied to cancer, then immune activation occurs, but lack of tumor-selective targeting causes off-target effects
Solution Approach 1:
The CAR construct is engineered with local quality through its antigen-binding domain that specifically recognizes TIM-1. This ensures that immune cell activation is spatially restricted to locations where TIM-1 is expressed on tumor cells, providing precise tumor-selective targeting while avoiding activation against healthy tissues and reducing off-target effects.
Data Source
AI summary
The invention provides chimeric antigen receptors (CARs) that specifically bind to the T-cell immunoglobulin and mucin domain 1 (TIM-1) protein. The invention further relates to modified immune cells, e.g., T or NK cells, comprising such CARs, CAR-encoding nucleic acids, CAR-encoding vectors, and methods of making such compositions. The invention further relates to methods for therapeutic use of these CARs and modified immune cells for the treatment of a condition, disorder, or disease associated with cells expressing TIM-1 (e.g., cancer).