Fully Human ROR1 CARs for Persistent T Cell Therapy
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Solution Overview
Problem
Current cancer treatments, particularly for solid tumors, face challenges in achieving durable responses due to limited in vivo expansion and persistence of CAR-T cells, rapid disappearance of CAR+ T cells after infusion, and disappointing clinical activity, largely attributed to the use of murine-derived CAR sequences and the need for subsequent hematopoietic stem cell transplantation.
Innovation Solution
Development of chimeric antigen receptors (CARs) containing high-affinity, fully human ROR1 antigen binding domains that exhibit high surface expression on transduced T cells, promoting in vivo expansion and persistence, and incorporating linker and intracellular signaling domains for enhanced therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If murine-derived CAR sequences are used, then CAR-T cells can be generated and infused, but they rapidly disappear after infusion and fail to achieve durable responses
Solution Approach 1:
The patent changes the origin of the CAR sequences from murine to fully human, fundamentally altering the immunogenicity parameters of the CAR-T cells. This parameter change allows the cells to evade anti-CAR immunity and persist longer in vivo, directly addressing the rapid disappearance problem while improving treatment durability
Solution Approach 2:
The patent converts the potential harm of immune recognition (which causes rapid clearance) into a benefit by designing fully human CAR sequences that are invisible to the human immune system. This allows the CAR-T cells to evade detection and elimination, transforming the immune system from a harmful clearing mechanism into a tolerant environment that supports long-term persistence
2Productivity
If CAR-T cells are infused to treat cancer, then they can target and kill tumor cells, but they fail to expand and persist in vivo sufficiently
Solution Approach 1:
The patent changes the species origin parameter of the CAR sequences from murine to fully human, which fundamentally alters the in vivo behavior of the CAR-T cells. This parameter change enables the cells to evade immune-mediated elimination, allowing them to expand and persist at therapeutic levels while maintaining their cytolytic activity against ROR1-expressing tumor cells
3Strength
If high-affinity ROR1 antigen binding domains are used, then CAR-T cells show high cytolytic activity, but they may trigger anti-CAR immunity that reduces persistence
Solution Approach 1:
The patent changes the amino acid sequence origin of the ROR1 antigen binding domains from murine to fully human, which fundamentally alters the immunogenicity profile. This parameter change allows the high-affinity binding domains to maintain their strong cytolytic activity while becoming invisible to the human immune system, thereby eliminating the anti-CAR immunity response that would otherwise limit persistence
Data Source
AI summary
Chimeric antigen receptors containing ROR1 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.