ROR1-Targeting CAR T Cells with c-Jun for Exhaustion Resistance
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Solution Overview
Problem
Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells is limited by T cell exhaustion, which reduces the efficacy of cancer treatment.
Innovation Solution
A polynucleotide encoding a chimeric polypeptide comprising a c-Jun polypeptide, a ROR1-binding protein, and a truncated EGF receptor (EGFRt) is expressed in cells to prevent or reduce exhaustion, enhancing the persistence and efficacy of CAR T cells by incorporating a c-Jun polypeptide with specific amino acid sequences and a ROR1-binding protein with defined variable regions, along with a spacer and intracellular signaling domains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used for adoptive immunotherapy, then tumor cell recognition and killing capability is improved, but T cell exhaustion occurs reducing treatment efficacy
Solution Approach 1:
The patent changes the molecular parameters of the T cell by introducing a chimeric polypeptide with specific amino acid sequences (at least 60% identity to SEQ ID NO: 1) that modifies T cell exhaustion resistance. This parameter change enables the T cell to maintain functionality longer while recognizing and killing tumor cells expressing ROR1.
Solution Approach 2:
The patent creates a composite chimeric polypeptide structure combining multiple functional domains: an ROR1-binding protein domain (specifically binding ROR1 on tumor cells), a c-Jun polypeptide domain (providing exhaustion resistance), and a truncated EGF receptor domain (EGFRt). This composite structure integrates tumor targeting, persistence enhancement, and safety functions into a single molecular entity expressed in the T cell.
2Measurement precision
If CAR T cells are engineered to recognize ROR1, then specificity against tumor cells is improved, but T cell exhaustion limits long-term efficacy
Solution Approach 1:
The patent merges two critical functions into a single chimeric polypeptide: ROR1-specific antigen recognition (providing measurement precision/specificity) and exhaustion resistance (providing reliability/efficacy). The c-Jun containing chimeric polypeptide simultaneously enables specific tumor cell targeting and prevents T cell exhaustion, resolving the contradiction between specificity and long-term efficacy.
Solution Approach 2:
The patent modifies the molecular parameters of the T cell receptor by introducing a chimeric polypeptide with defined amino acid sequence identity requirements (at least 60% to SEQ ID NO: 1). This parameter change enhances both the specificity of ROR1 recognition and the reliability of treatment by preventing exhaustion.
3Duration of action of moving object
If chimeric polypeptide with c-Jun is expressed, then exhaustion resistance is improved, but cellular function and proliferation are enhanced
Solution Approach 1:
The patent converts the typically harmful effect of T cell exhaustion into a beneficial sustained effector function. The c-Jun containing chimeric polypeptide prevents exhaustion, transforming what would be a limiting factor into an advantage where T cells maintain both persistence and high-level cytokine production and effector functions against ROR1-expressing tumor cells.
Data Source
AI summary
The present disclosure relates to polynucleotides encoding a chimeric polypeptide comprising a c-Jun polypeptide, a ROR1-binding protein, and a truncated EGF receptor. Also provided are cells (e.g., T cells) expressing CARs comprising a ROR1-binding protein and overexpressing a c-Jun polypeptide. Overexpression of c-Jun in CAR T cells confers improved properties, e.g., reducing or preventing exhaustion.