Chimeric PD-1 4-1BB Receptor for TCR T Cell Persistence
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current immunotherapies targeting cancer antigens like PRAME and NY-ESO-1 face challenges due to the immunosuppressive tumor microenvironment, which inhibits the efficacy and persistence of TCR-modified T cells, particularly in solid tumors, where the PD-1/PD-L1 axis reduces T cell infiltration and leads to exhaustion.
Innovation Solution
Development of polyfunctional immune cells expressing high avidity TCRs specific for PRAME or NY-ESO-1 peptides combined with a chimeric co-stimulatory receptor comprising a PD-1 extracellular domain and a 4-1BB intracellular domain, enhancing cytokine release, proliferation, and cytotoxicity while reversing the inhibitory PD-1/PD-L1 checkpoint.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If TCR-modified T cells are used to target cancer antigens, then antigen specificity is improved, but the immunosuppressive tumor microenvironment causes T cell exhaustion and reduced efficacy
Solution Approach 1:
The patent combines a TCR with high antigen specificity for cancer antigens (PRAME or NY-ESO-1) with a chimeric co-stimulatory receptor (comprising PD-1 extracellular domain and 4-1BB intracellular domain) into a single engineered T cell. This merging allows the T cell to simultaneously achieve high antigen recognition capability and resistance to PD-1-mediated inhibition in the tumor microenvironment, resolving the contradiction between specificity and efficacy.
Solution Approach 2:
The engineered T cell expresses a composite receptor system that integrates the antigen-specific recognition function of the TCR with the co-stimulatory and checkpoint-blocking functions of the chimeric PD-1/4-1BB receptor. This composite receptor architecture enables the T cell to maintain high antigen specificity while simultaneously overcoming the immunosuppressive effects of the tumor microenvironment.
2Measurement precision
If high avidity TCRs are used to enhance tumor cell recognition, then targeting precision is improved, but T cell exhaustion in the immunosuppressive microenvironment worsens
Solution Approach 1:
The chimeric co-stimulatory receptor with 4-1BB intracellular domain provides preliminary protective action against PD-1-mediated inhibition before the T cell encounters exhaustion signals in the tumor microenvironment. The 4-1BB signaling pathway preemptively enhances T cell survival, proliferation, and metabolic function, counteracting the harmful effects of PD-1 engagement and preventing exhaustion.
Solution Approach 2:
The patent converts the harmful PD-1 inhibition pathway into a beneficial effect by using the extracellular domain of PD-1 in the chimeric receptor to bind PD-L1 on tumor cells, while the intracellular 4-1BB domain transmits activating signals. This reverses the normal inhibitory function of PD-1 into a co-stimulatory signal, transforming the harmful checkpoint inhibition into a benefit that enhances T cell function and prevents exhaustion.
3Power
If T cells are equipped with antigen-specific TCRs, then cytokine release and cytotoxicity are enhanced, but persistence in the tumor microenvironment is reduced
Solution Approach 1:
The chimeric co-stimulatory receptor alters key parameters of T cell biology including survival signaling, metabolic function, and proliferation capacity. The 4-1BB intracellular domain activates NF-κB and other survival pathways that change the T cell's physiological state from one prone to exhaustion to one with enhanced persistence capabilities, allowing sustained cytokine release and cytotoxicity over extended periods in the tumor microenvironment.
Data Source
AI summary
The present invention refers immune cells expressing a TCR and a co-stimulatory receptor which are poly functional, i.e. secreting 2 or more proteins. Exemplary immune cells express a(i) T cell receptor (TCR) specific for the PRAME peptide SLLQHLIGL or a TCR specific for NY-ESO-1 peptide SLLMWITQC and (ii) a chimeric co-stimulatory receptor comprising an extracellular domain derived from PD-1 (CD279) and an intracellular domain derived from 4-1BB (CD137).