Inducible Dominant Negative PD-1 in CAR-T Therapy
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Solution Overview
Problem
Current immune therapies face challenges in effectively modulating the deletion or genetic absence of PD-1 or other inhibitory immune checkpoint molecules in T-cells, which can negatively impact long-lived memory compartment and long-term efficacy of T-cell based therapies.
Innovation Solution
Development of modified cells expressing a dominant negative form of inhibitory immune checkpoint molecules, regulated by an inducible gene expression system, along with nucleic acids encoding binding molecules to enhance T-cell response and cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If PD-1 or other inhibitory immune checkpoint molecules are deleted or genetically absent in T-cells, then T-cell response is enhanced, but long-lived memory compartment is negatively impacted
Solution Approach 1:
The patent applies dynamic control by making PD-1 expression inducible rather than static deletion. The modified T-cells can dynamically adjust PD-1 expression levels based on treatment phase: high expression during activation to prevent exhaustion, and low expression during memory formation to ensure persistence. This temporal dynamics resolves the contradiction between enhancing acute T-cell response and preserving long-term memory.
Solution Approach 2:
The patent implements periodic action through staged modulation of PD-1 expression. During the initial treatment phase, PD-1 is suppressed to maximize T-cell activation and cytotoxicity. As treatment progresses and memory formation begins, PD-1 expression is gradually restored to maintain memory cell persistence. This periodic switching between suppression and restoration phases resolves the contradiction between acute efficacy and long-term durability.
2Productivity
If PD-1 is blocked to enhance T-cell response, then cancer treatment efficacy is improved, but long-term persistence of T-cells is reduced
Solution Approach 1:
The patent applies preliminary action by pre-establishing the inducible expression system in T-cells before treatment begins. This allows the system to be primed for rapid response modulation: PD-1 can be quickly suppressed when T-cell activation is needed, and equally quickly restored when persistence is required. The preliminary setup of this controllable system enables flexible adaptation throughout the treatment course without compromising either acute response or long-term persistence.
3Productivity
If genetic absence of PD-1 is achieved, then T-cell activation is enhanced, but reprogramming capability is prevented
Solution Approach 1:
The patent applies parameter changes by precisely controlling the expression level of PD-1 rather than complete deletion. By adjusting PD-1 expression to specific levels at different time points, the system optimizes T-cell activation parameters during treatment while preserving reprogramming capability for memory formation. This quantitative control of the PD-1 parameter allows simultaneous achievement of enhanced activation and maintained adaptability.
Data Source
AI summary
Embodiments relate to a modified cell comprising a chimeric antigen receptor (CAR) and a dominant negative form of PD-1, wherein the dominant negative form of PD-1 lacks a functional PD-1 intracellular domain for PD-1/PD-L1 signal transduction, and the CAR comprises an antigen binding domain, a transmembrane domain, a co-stimulatory domain, and a CD3 zeta domain. The dominant negative form of PD-1 is regulated by an inducible gene expression system.