CAR T-Cell Composition With Dominant Negative PD-1 for Solid Tumors
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Solution Overview
Problem
Existing immunotherapy methods for cancer treatment face challenges due to the immunosuppressive tumor microenvironment that limits therapeutic immune cell access and effectiveness, particularly in solid tumors, where malignant cells adapt to evade immune recognition and elimination.
Innovation Solution
Development of immune cells or precursor cells that recombinantly express a chimeric antigen receptor (CAR) and a dominant negative form of PD-1, which lacks a signaling domain, to enhance tumor infiltration and overcome immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T-cell therapy is used to treat solid tumors, then tumor antigen binding is improved, but immune cell infiltration and function are inhibited by the immunosuppressive tumor microenvironment
Solution Approach 1:
The patent applies preliminary anti-action by pre-equipping CAR T-cells with dominant negative forms of immune checkpoint inhibitors (such as PD-1, CTLA-4, TIM-3, LAG-3) before their introduction into the tumor microenvironment. This preemptive genetic modification allows the T-cells to resist suppressive signals before they are encountered, counteracting the immunosuppressive environment's harmful effects on CAR T-cell function and persistence
Solution Approach 2:
The patent creates composite immune cells by combining multiple functional elements within a single T-cell: (1) the CAR receptor for antigen recognition and activation, (2) dominant negative forms of multiple immune checkpoint inhibitors for resistance to suppression, and (3) optionally costimulatory molecules. This composite structure enables the T-cell to simultaneously perform antigen targeting, immune activation, and resistance to tumor-induced suppression
2Reliability
If immune checkpoint inhibitors are added to enhance resistance to suppression, then T-cell persistence and function are improved, but device complexity increases
Solution Approach 1:
The patent merges multiple therapeutic functions into a single genetically modified T-cell product. By combining the CAR receptor with dominant negative forms of immune checkpoint inhibitors (PD-1, CTLA-4, TIM-3, LAG-3) within the same cell, the therapy achieves both antigen targeting and resistance to suppression through one cellular product, simplifying the overall treatment approach despite the increased molecular complexity within the cell
Solution Approach 2:
The dominant negative forms of immune checkpoint inhibitors serve multiple protective functions simultaneously. For example, a dominant negative PD-1 can block both PD-L1 and PD-L2 interactions, while also preventing self-inhibition. This multi-functionality reduces the need for separate modifications for each checkpoint pathway, managing complexity while maintaining broad protective coverage
3Productivity
If CAR T-cells are administered to overcome immune suppression, then tumor infiltration is enhanced, but therapeutic efficacy is limited by checkpoint inhibition
Solution Approach 1:
The patent performs preliminary action by pre-modifying CAR T-cells with dominant negative forms of immune checkpoint inhibitors before their administration and activation in the tumor microenvironment. This advance preparation ensures that when the T-cells encounter suppressive signals during tumor infiltration, they are already equipped to resist these signals, maintaining their cytotoxic function and therapeutic efficacy throughout the infiltration process
Data Source
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Figure 1E
AI summary
Disclosed herein are cells that are immune cells or precursor cells thereof, which cells recombinantly express a chimeric antigen receptor (CAR), and a dominant negative form of an inhibitor of a cell-mediated immune response of the immune cell, wherein the CAR binds to a cancer antigen. Also disclosed herein are T cells that recognize and are sensitized to a cancer antigen, which T cells recombinantly express a dominant negative form of an inhibitor of a T cell-mediated immune response. Additionally provided are methods of using such cells to treat cancer in a subject in need thereof.