CAR T Cell Modified Hinge and Transmembrane Domain for Reduced Cytokine Release
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current CAR T cell therapy for cancer treatment faces challenges such as severe cytokine release syndrome, limited persistence of CD28-based CAR T cells, and suboptimal efficacy in solid tumors, particularly in high-risk B cell malignancies and non-Hodgkin's lymphoma, necessitating optimization of CAR structural elements to enhance effectiveness and reduce toxicity.
Innovation Solution
A chimeric antigen receptor (CAR) with a modified CD8 hinge and transmembrane domain (HTM-1) is developed, comprising an antigen binding domain, a costimulatory domain, and an intracellular signaling domain, designed to reduce pro-inflammatory cytokine release and enhance tumor cell killing while maintaining persistence, specifically targeting CD19-positive cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Power
If CD28-based CAR T cells are used, then strong T cell activation and effector-like phenotype are achieved, but in vivo persistence is limited and activation-induced cell death increases
Solution Approach 1:
The patent modifies the CAR T cell construct by changing the costimulatory domain from CD28 to 4-1BB, which fundamentally alters the activation parameters and signaling characteristics. This parameter change enables the CAR T cells to achieve sustained persistence in vivo while maintaining appropriate effector function, resolving the contradiction between strong activation and limited persistence.
2Duration of action of stationary object
If 4-1BB-based CAR T cells are used, then in vivo persistence is improved, but effector response is slower
Solution Approach 1:
The patent employs a dynamic costimulatory domain configuration by combining 4-1BB with CD28, creating a system where the CAR T cells can adapt their response characteristics. This dual-costimulatory approach allows the cells to exhibit both persistent memory-like survival and enhanced effector response capability, resolving the contradiction between persistence and response speed.
3Productivity
If CAR T cells with high cytotoxic activity are generated, then tumor killing efficacy is improved, but cytokine release syndrome severity increases
Solution Approach 1:
The patent incorporates costimulatory domains that provide regulated feedback signaling, allowing the CAR T cells to modulate their cytotoxic activity based on contextual cues. This feedback mechanism enables maintained tumor killing efficacy while preventing excessive cytokine release, as the costimulatory signals regulate the magnitude and duration of effector functions.
4Object-affected harmful factors
If CAR structural elements are modified to reduce cytokine release, then safety is improved, but therapeutic efficacy may be compromised
Solution Approach 1:
The patent creates a composite costimulatory domain system combining 4-1BB and CD28, where each domain contributes specific functional properties. This composite approach allows the CAR T cells to achieve both reduced cytokine release (improved safety) and maintained therapeutic efficacy, as the combined signaling pathways provide balanced regulation of effector functions.
Data Source
AI summary
The present disclosure provides a chimeric antigen receptor (CAR) molecule comprising a modified hinge and transmembrane domain (HTM-1), wherein the modified hinge and transmembrane domain comprises the amino acid sequence of SEQ ID NO:2. Cells expressing CAR with the modified HTM-1 domain disclosed herein are expected to have enhanced anti-tumor activities with reduced release of pro-inflammatory cytokines.