Synthetic Pathway Activators for CAR-T Expansion and Persistence
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Solution Overview
Problem
Current CAR-T cell-based immunotherapy for treating solid tumors faces challenges in achieving robust T cell expansion, persistence, and potency, limiting its effectiveness.
Innovation Solution
Development of synthetic pathway activator (SPA) peptides comprising a chimeric polypeptide with an extracellular domain, lipid anchor, transmembrane domain, and intracellular signaling domain, including multimerization regions that induce constitutive activity, enhancing T cell activation and potency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are used to treat solid tumors, then T cells can recognize and target tumor cells, but robust T cell expansion, persistence, and potency are not achieved
Solution Approach 1:
The invention divides the T cell activation process into multiple independent signaling domains within the CAR structure. The CAR includes a first intracellular signaling domain (e.g., CD3ζ) for T cell activation and a second intracellular signaling domain (e.g., costimulatory domains like 4-1BB or CD28) for enhanced T cell expansion and persistence. This segmentation allows each domain to independently contribute to different aspects of T cell function, resolving the contradiction between reliable T cell expansion and antitumor productivity.
Solution Approach 2:
The CAR-T cell receptor is constructed as a composite chimeric protein combining extracellular antigen-binding domains (e.g., scFv) with multiple intracellular signaling domains. This composite structure integrates signals from different sources (antigen recognition + costimulation) to achieve both robust T cell expansion/persistence and potent antitumor activity, overcoming the limitations of single-domain CAR designs.
2Adaptability or versatility
If T cells are genetically engineered to produce chimeric antigen receptors, then T cells gain new ability to target specific proteins, but additional therapies are needed to increase T cell expansion, persistence, and potency
Solution Approach 1:
The invention merges the antigen recognition function (extracellular scFv domain) with multiple intracellular signaling functions (CD3ζ domain for activation plus costimulatory domains for expansion and persistence) into a single integrated CAR molecule. This merging ensures that T cells engineered with the CAR simultaneously gain both the adaptability to target specific proteins and the reliability of robust expansion and persistence without requiring separate therapeutic interventions.
Data Source
AI summary
Provided herein are novel synthetic pathway activators comprising multimerization regions, transmembrane domains, and intracellular signaling domains.