CRISPR deletion of endogenous T cell receptor chains for optimized immunotherapies

This technology is a CRISPR-based method for deleting endogenous T cell receptor (TCR) chains while preserving transgenic TCR functionality, enabling safer and more effective T cell therapies and the development of CAR-T cells.

Unmet Need: Safe and efficient T cell receptor replacement in T cells

Current methods for T cell therapy often involve genetic modifications that retain the endogenous T cell receptor (TCR). This can lead to mispairing with transgenic TCRs, reduced therapeutic efficacy, and potential autoimmune reactions. CRISPR-based approaches exist but struggle to effectively target both alpha and beta chains of the TCR and distinguish between endogenous and transgenic TCRs. Additionally, autologous CAR-T cell therapies are expensive and time-consuming to manufacture, limiting accessibility for patients. Addressing these limitations is critical to improve the safety, efficiency, and scalability of T cell therapies.

The Technology: CRISPR-based method for deleting endogenous T cell receptor chains

This technology is a CRISPR-based method to delete both the alpha and beta chains of the endogenous T cell receptor (TCR) without affecting the transgenic TCR. The endogenous TCR is deleted using CRISPR-based guide RNAs that target the intron-exon boundaries of the constant regions. The method preserves the integrity of the transgenic TCR, which lacks introns, ensuring its functionality is unaffected. By eliminating endogenous TCRs, this approach prevents mispairing and reduces the risk of generating receptors with unknown specificities. Additionally, the technology can be seamlessly integrated with transgenic TCR viral vectors to simultaneously delete endogenous TCRs and introduce transgenic TCR constructs.

This technology has been validated with human cancer cell lines.

Applications:

• Allogeneic CAR-T cell manufacturing
• Safer T cell receptor (TCR)-engineered T cell therapies
• Prevention of graft-versus-host disease
• Research tool for T cell engineering
• Drug screening for immunotherapy optimization
• Development of cost-effective off-the-shelf therapies

Advantages:

• Efficient deletion of endogenous TCR chains
• Preserves transgenic TCR functionality
• Prevents mispairing of TCR chains
• Compatible with existing TCR viral vectors
• Enables cost-effective off-the-shelf CAR-T cells
• Reduces risk of autoimmune reactions
• Improves safety of T cell therapies

Lead Inventor:

Megan Sykes, M.D.

Patent Information:

Patent Pending (WO/2024/2588835)

Related Publications:

Tech Ventures Reference:

• IR CU20245, CU23372

• Licensing Contact: Jerry Kokoshka