Allogeneic CD19 CAR T Cells With HLA-E Shielding Against Rejection
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Solution Overview
Problem
Current CAR T cell therapies face challenges with patient-specific manufacturing for autologous delivery and high relapse rates due to antigen escape and tumor cell heterogeneity, particularly in allogenic administration.
Innovation Solution
Genetically engineered T cells with disruptions in the TRAC and B2M genes, expression of a single chain HLA-E fusion protein, and a chimeric antigen receptor (CAR) directed against CD19, using CRISPR-Cas systems for gene editing, to reduce immune recognition and enhance targeting efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If autologous CAR T cell therapy is used, then patient-specific manufacturing is required, but manufacturing complexity and time are increased
Solution Approach 1:
The patent creates allogeneic CAR T cells that copy the successful autologous therapy approach but uses donor cells instead of patient cells. This allows the therapy to be manufactured once and used universally, eliminating the need for patient-specific manufacturing while maintaining therapeutic efficacy through standardized production processes
Solution Approach 2:
The patent develops universal allogeneic CAR T cell products that can be used across multiple patients with the same cancer type. The standardized manufacturing process and donor cell source create a universal therapy that eliminates the need for individual customization, reducing manufacturing complexity and enabling scalable production
2Device complexity
If single antigen targeting is used, then CAR design is simplified, but relapse rate increases due to antigen escape and tumor heterogeneity
Solution Approach 1:
The patent divides the CAR T cell therapy into multiple functional components: different CAR variants targeting different antigens, combined with checkpoint inhibitors and other immunomodulatory agents. This segmented approach allows each component to address specific aspects of tumor targeting, preventing antigen escape and overcoming tumor heterogeneity without overcomplicating any single element
Solution Approach 2:
The patent creates a composite therapy system combining multiple CAR T cell lines with different antigen specificities, checkpoint inhibitors, and immunomodulators. This composite approach leverages the strengths of each component to achieve comprehensive tumor targeting and prevent relapse, addressing the limitations of single-antigen CARs while maintaining manageable complexity through modular design
3Productivity
If allogeneic CAR T cells are used, then manufacturing scalability is improved, but immune recognition and rejection increase
Solution Approach 1:
The patent extracts and removes endogenous MHC class I molecules from the donor T cells through genetic disruption of the B2M gene. This extraction eliminates the primary target for NK cell recognition and host immune rejection, allowing allogeneic cells to proliferate and persist in the patient without triggering harmful immune responses while maintaining manufacturing scalability
Solution Approach 2:
The patent introduces heterologous MHC class I molecules (such as HLA-E) as intermediary elements that serve as decoy targets for NK cell inhibitory receptors. These intermediary molecules bind to NK cell inhibitory receptors, preventing them from recognizing and attacking the allogeneic T cells, thereby mediating protection against immune rejection while preserving the scalability benefits of allogeneic manufacturing
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The engineered T cells achieve reduced immune recognition and improved persistence, enhancing therapeutic efficacy against cancer by minimizing antigen escape and heterogeneity.
Implementation Method 1
using CRISPR-Cas systems for gene editing
Implementation Method 2
a chimeric antigen receptor (CAR) directed against CD19
Implementation Method 3
expression of a single chain HLA-E fusion protein
Data Source
AI summary
Provided herein are genetically engineered T cells containing a chimeric antigen receptor (CARs), and related methods and uses thereof in allogeneic cell therapy. In some embodiments, the T cells are genetically engineered with a CAR and are further genetically engineered by one or more strategies to reduce host immune recognition of the engineered T cells, such as by heterologous expression of one or more additional transgenes and by genetic disruption to reduce or eliminate expression or one or more endogenous protein. Also provided are cell compositions containing the engineered T cells, and related methods, kits and systems for producing the engineered T cells. Also provided are methods of making and using the engineered T cells for cell therapy, including in connection with cancer immunotherapy comprising adoptive transfer of the engineered T cells.