Compositions for identification of membrane targets for enhancement of T cell activity against cancer
Inventors
Chen, Sidi • Ye, Lupeng • Park, Jonathan • Dong, Matthew • Chow, Ryan D.
Assignees
Publication Number
US-12297428-B2
Publication Date
2025-05-13
Expiration Date
2039-07-31
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Abstract
The present invention includes compositions and methods for identification of membrane targets for enhancement of T cell activity against a disease, disorder or condition, and/or enhancing T cell anti-tumor activity in a subject in need thereof. In some embodiments, the disease is cancer. In further embodiments, the cancer is glioblastoma (GBM) or breast cancer.
Core Innovation
The invention provides compositions and methods for the identification of membrane-bound targets for enhancement of T cell activity against diseases, disorders, or conditions, with a focus on cancers such as glioblastoma (GBM) and breast cancer. The technology includes engineered sgRNA libraries (such as mmSurf and mSURFEOME2) targeting thousands of membrane-bound molecules, packaged into adeno-associated virus (AAV) vectors for high-throughput CRISPR-based gene screening and editing. These libraries enable the precise targeting of genes involved in T cell regulation and anti-tumor activity.
A core aspect of the invention is the use of AAV vectors carrying CRISPR systems for the efficient gene editing and high-throughput screening of T cells to identify membrane protein targets that can be manipulated to enhance the anti-tumor functions of T cells. The invention enables the creation and delivery of genetically modified T cells—where one or more specific genes (such as Mgat5, Pdia3, Lag3, and Emp1) are targeted or mutated—and includes methods for their administration to a subject in need.
The problem addressed is the urgent unmet need for novel therapeutics and targets to enhance T cell anti-tumor activity, especially for cancers resistant to current immunotherapies. Current immunotherapy approaches in GBM, such as immune checkpoint blockade or CAR-T therapies, have failed to significantly improve survival, revealing a need for new strategies to identify and modulate previously unrecognized targets that impact CD8+ T cell anti-tumor function. The disclosed inventions are designed to address these limitations by enabling the systematic and functional screening of the T cell surfaceome to discover new therapeutic targets.
Claims Coverage
The patent discloses a single inventive feature in its independent claim.
AAV vector comprising SEQ ID NO: 69,821
The inventive feature is an adeno-associated virus (AAV) vector comprising the nucleic acid sequence set forth in SEQ ID NO: 69,821. - This sequence codes for elements enabling CRISPR/Cas9-mediated gene editing and high-throughput screening in T cells, as described in the detailed description and summary. - The invention is defined strictly by the inclusion of SEQ ID NO: 69,821 within the AAV vector. - The claim covers the AAV vector structure without restriction by intended use or specific application.
The inventive coverage is limited to the AAV vector containing SEQ ID NO: 69,821 as specified in claim 1.
Stated Advantages
The compositions and methods enable efficient identification of membrane protein targets on T cells to enhance anti-tumor activity.
The invention allows high-throughput CRISPR screening in primary T cells using AAV delivery systems.
Gene editing with the disclosed vectors enables production of genetically modified T cells with enhanced therapeutic potential.
Documented Applications
Enhancing T cell (including CD8+, CD4+, Treg, and CAR-T cells) anti-tumor activity in cancers such as glioblastoma and breast cancer.
Treatment of a wide variety of cancers, including but not limited to GBM, breast cancer, triple-negative breast cancer, and those listed in Table 6.
Genome editing and screening of T cells in vitro and in vivo using AAV-CRISPR vectors for the identification of gene targets.
Generation of genetically modified T cells for therapeutic administration to subjects in need.
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