Mesothelin-Targeted CARs for Solid Tumor Killing With Lower Toxicity
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Solution Overview
Problem
Existing CAR-expressing T cell therapies face challenges in effectively targeting and eradicating solid tumors due to immunosuppressive microenvironments and anatomical barriers, as well as the need for optimal immune targets that minimize toxicity and immunogenicity.
Innovation Solution
Development of chimeric antigen receptors (CARs) specifically targeting human mesothelin with enhanced binding affinity and co-stimulatory domains, such as CD28 or 4-1BB, to enhance T cell activation and tumor infiltration, combined with immunoresponsive cells expressing cytokines and adhesion molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-expressing T cell therapy is used to target solid tumors, then tumor eradication capability is improved, but toxicity and immunogenicity increase
Solution Approach 1:
The patent applies local quality by designing CARs with selective antigen recognition that specifically targets tumor-associated antigens (such as Mesothelin, EGFRvIII, or Wilms tumor antigen) while sparing normal tissues. This is achieved through careful selection of antigen-specific binding domains and optimization of binding affinity to ensure the CAR-T cells activate primarily at the tumor site rather than causing systemic toxicity.
Solution Approach 2:
The patent employs parameter changes by systematically optimizing multiple CAR design parameters including: (1) antigen binding affinity constants, (2) co-stimulatory domain configurations (CD28, 4-1BB, or OX40), (3) intracellular signaling domain compositions, and (4) transgene expression levels. These parameter optimizations enable titration of CAR-T cell activity to achieve maximum tumor killing while minimizing off-target effects and immunogenicity.
2Strength
If CAR design is optimized for potent tumor killing, then anti-tumor activity is improved, but CAR-induced toxicity increases
Solution Approach 1:
The patent applies dynamics by incorporating inducible or regulatable elements into the CAR design that allow the anti-tumor activity to be dynamically controlled. This includes using promoters responsive to tumor microenvironment signals or incorporating suicide gene switches that enable temporary high-activity states for tumor killing followed by rapid deactivation if toxicity emerges, thus decoupling peak anti-tumor activity from sustained toxicity.
Solution Approach 2:
The patent uses intermediary mechanisms by introducing co-stimulatory domains (CD28, 4-1BB, OX40) that act as intermediaries between antigen recognition and full T cell activation. These intermediaries provide a controlled amplification step that enhances anti-tumor activity only when both antigen binding and co-stimulatory signals are present, thereby reducing unintended activation and toxicity while maintaining potent tumor killing capability.
3Reliability
If T cell activation is enhanced to overcome immunosuppressive microenvironment, then tumor infiltration capability is improved, but immunogenicity increases
Solution Approach 1:
The patent applies preliminary action by pre-conditioning the CAR-T cells with specific co-stimulatory signals or cytokine priming before adoptive transfer. This preliminary activation enhances the cells' ability to infiltrate immunosuppressive tumor microenvironments by pre-upregulating adhesion molecules and chemokine receptors, while the controlled nature of this pre-activation reduces subsequent immunogenicity compared to strong in vivo activation.
Data Source
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AI summary
The presently disclosed subject matter provides for methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to chimeric antigen receptors (CARs) that specifically target human mesothelin, and immunoresponsive cells comprising such CARs. The presently disclosed mesothelin-targeted CARs have enhanced immune-activating properties, including anti-tumor activity. To be accompanied, when published, by Figure 1 of the drawings.