CAR T Cells With CD8a Domains Targeting Osteosarcoma
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Solution Overview
Problem
Current CAR T cell therapies face challenges in effectively targeting and treating osteosarcoma, a aggressive form of bone cancer, due to issues such as poor trafficking to tumors, enhanced immunosuppressive mechanisms, and severe side effects.
Innovation Solution
Development of novel chimeric antigen receptors (CARs) that recognize a lung metastasis-specific marker, combined with a CD8a hinge domain, CD8a transmembrane domain, and an intracellular signaling domain comprising a CD3ζ signaling domain and a 4-1BB costimulatory domain, to enhance the therapeutic efficacy of CAR T cells against osteosarcoma.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used to target osteosarcoma, then antitumor activity is achieved, but severe side effects occur including respiratory distress and death
Solution Approach 1:
The patent applies local quality by designing a CAR construct with specific local characteristics: a CD8α hinge domain and CD8α transmembrane domain that are locally optimized for bone marrow homing and osteosarcoma targeting. This localized structural optimization enables the CAR T cells to specifically target osteosarcoma cells while minimizing off-target effects on healthy tissues, thereby reducing severe side effects while maintaining antitumor activity
Solution Approach 2:
The patent applies parameter changes by modifying key parameters of the CAR construct, specifically using a CD8α hinge domain and CD8α transmembrane domain instead of conventional domains. These parameter changes in the CAR structure fundamentally alter the behavior and targeting specificity of the T cells, enabling them to home to bone marrow and selectively target osteosarcoma cells with reduced toxicity to healthy tissues
2Ease of operation
If CAR T cells are administered intravenously, then systemic distribution is achieved, but poor trafficking to tumor sites occurs
Solution Approach 1:
The patent applies local quality by incorporating a CD8α hinge domain and CD8α transmembrane domain in the CAR construct, which are locally optimized to enable the T cells to home to bone marrow and effectively traffic to osteosarcoma sites. This localized structural optimization ensures that intravenously administered CAR T cells can successfully navigate to tumor sites while maintaining systemic distribution
Solution Approach 2:
The patent applies the intermediary principle by using the CD8α hinge and transmembrane domains as intermediary structures that facilitate the interaction between the CAR T cells and the osteosarcoma microenvironment. These intermediary domains act as mediators that enable effective trafficking and homing to tumor sites while maintaining systemic distribution after intravenous administration
3Measurement precision
If the antigen binding domain is optimized for high affinity, then target recognition is improved, but specificity to healthy tissues may be compromised
Solution Approach 1:
The patent applies local quality by designing an antigen binding domain with specific local characteristics that achieve high affinity for osteosarcoma-associated antigens while maintaining specificity. The localized optimization of the antigen binding domain ensures precise target recognition of osteosarcoma cells without compromising safety by reacting with healthy tissues
Solution Approach 2:
The patent applies the intermediary principle by using the CD8α hinge and transmembrane domains as intermediary structures that facilitate the interaction between the antigen binding domain and the osteosarcoma microenvironment. These intermediary domains act as mediators that enable effective target recognition while maintaining specificity and reducing off-target effects
Data Source
AI summary
Chimeric antigen receptors (CARs) are provided. When the CARs herein are expressed on the surface of immune cells, such immune cells may be directed to osteosarcoma cells. In a murine intraperitoneal model, the tumor growth was significantly delayed for T cells expressing a CAR comprising a scFv from TP1 or TP3 antibodies. Immune cells expressing the CARs herein display therapeutic effect in the form of decreased tumor volume in a murine model simulating metastatic osteosarcoma. Combined with the finding that stem cells from healthy bone marrow were not significantly affected by T cells expressing any of the CARs, the CARs may be used for the treatment of osteosarcoma.