TAPi And RNAi Cell Therapy Compositions for Immune Evasion
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Solution Overview
Problem
Adoptive cell therapies, such as CAR-T cell therapy, face challenges due to patient immune responses against non-self components, leading to limited persistence and efficacy, especially with allogeneic immune effector cells, necessitating complex gene editing and deep host immune suppression.
Innovation Solution
Engineering CAR-T cells to express an inhibitor of transporter associated with antigen processing (TAPi) and reduce MHC class I expression, combined with RNAi targeting MHC class II transactivator protein to decrease immune response without requiring deep host immune suppression or complex gene editing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If deep host immune suppression is used to prevent immune response to CAR-T cells, then immune response is reduced, but treatment complexity and risk increase
Solution Approach 1:
The patent converts the harmful immune response into a beneficial outcome by engineering CAR-T cells to express viral TAPi proteins that actively suppress MHC class I expression on the cell surface. This allows the CAR-T cells to evade detection by host immune systems without requiring external immune suppression therapies, thus converting the problem of immune recognition into a solution where the therapeutic cells themselves control their own immune evasion
Solution Approach 2:
The patent introduces viral TAPi proteins as intermediary molecules that mediate between the CAR-T cells and the host immune system. These TAPi proteins act as decoys that bind to and inhibit host immune recognition pathways, specifically interfering with the presentation of CAR-T cell antigens via MHC class I molecules, thereby reducing immune rejection without requiring direct contact between CAR-T cells and suppressive therapies
2Object-affected harmful factors
If complex gene editing is performed to reduce MHC expression, then immune response is reduced, but manufacturing complexity and cost increase
Solution Approach 1:
The patent incorporates the viral TAPi protein expression cassette into the CAR construct itself, so that the immune evasion mechanism is established at the time of CAR-T cell manufacturing. This preliminary integration ensures that the TAPi protein is co-expressed with the CAR from the outset, eliminating the need for subsequent complex gene editing steps to reduce MHC expression and simplifying the overall manufacturing process
Solution Approach 2:
The patent merges the CAR expression construct with the viral TAPi protein expression cassette into a single integrated vector. This combination allows simultaneous expression of both the therapeutic CAR and the immune evasion TAPi protein in the same transduction step, reducing manufacturing complexity by eliminating the need for separate gene editing operations to achieve MHC downregulation
3Object-affected harmful factors
If MHC class I expression is reduced to evade immune detection, then immune response is reduced, but NK cell-mediated rejection increases
Solution Approach 1:
The patent modifies the expression level and pattern of MHC class I molecules by introducing viral TAPi proteins, which specifically inhibit the antigen processing pathway. This parameter change in MHC expression allows CAR-T cells to evade T cell-mediated immune recognition while maintaining enough MHC class I expression to avoid NK cell activation, finding an optimal balance between immune evasion and NK cell safety
4Adaptability or versatility
If allogeneic immune effector cells are used to increase patient access, then availability improves, but immune rejection risk increases
Solution Approach 1:
The patent converts the harmful allogeneic immune recognition into a beneficial outcome by engineering allogeneic CAR-T cells to express viral TAPi proteins that actively suppress MHC class I expression. This allows the allogeneic cells to evade detection by the patient's immune system, transforming the problem of allogeneic rejection into a solution where the therapeutic cells themselves control their own immune evasion, thereby enabling broader patient access
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 approach effectively reduces immune response to CAR-T cells, enhancing persistence and efficacy while minimizing NK cell-mediated rejection and maintaining therapeutic efficacy.
Implementation Method 1
engineering the cells of the adoptive cell therapy to express an inhibitor of transporter associated with antigen processing (TAPi) which decreases expression of MHC class I
Implementation Method 2
decreasing the expression of MHC class II (e.g. using RNAi targeting a MHC class II transactivator protein)
Data Source
AI summary
This application provides, in part, methods and compositions for decreasing the immunogenicity of cell therapies (e.g., CAR-T cell therapies) using inhibitors of transporter associated with antigen processing (TAPi) and oligonucleotides that decrease the expression of an immunogenic proteins (e.g., MHC Class I and Class II).