Microfluidic TIL Delivery for Cytokine-Independent Persistence
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Solution Overview
Problem
Current TIL therapies require patient lymphodepletion and high dose IL-2 maintenance post-infusion, limiting their applicability and potential for repeat dosing and concurrent treatments.
Innovation Solution
Modifying TILs to enhance expression of co-stimulatory molecules, cytokines, and anti-apoptotic factors through nucleic acid delivery using a cell-deforming constriction process, allowing increased expression of molecules like B7-H2, IL-15, and Bcl-2, thereby improving proliferation, persistence, and tumor cell killing capabilities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TILs are modified to enhance expression of co-stimulatory molecules, cytokines, and anti-apoptotic factors, then proliferation, persistence, and tumor cell killing capabilities are improved, but the complexity of the manufacturing process increases
Solution Approach 1:
The patent uses microfluidic constrictions as an intermediary device to deliver nucleic acids into TILs. The microfluidic system acts as a mediator that enables genetic modification without requiring complex viral transduction protocols or multiple transfection steps, thereby improving TIL functionality while managing manufacturing complexity
Solution Approach 2:
The patent replaces complex biochemical transfection mechanisms with a mechanical microfluidic constriction system. By using physical deformation and pressure-driven nucleic acid delivery through microfluidic constrictions, the method simplifies the manufacturing process compared to traditional genetic engineering approaches
2Reliability
If TILs are engineered ex vivo with mRNA to enhance potency, then the therapeutic effect is improved, but the need for lymphodepletion and high dose IL-2 maintenance increases treatment complexity
Solution Approach 1:
The patent applies preliminary action by pre-engineering TILs with mRNA encoding co-stimulatory molecules, cytokines, and anti-apoptotic factors before adoptive transfer. This advance genetic modification enables the TILs to be self-sufficient, producing their own cytokines and survival signals, thereby reducing or eliminating the need for post-infusion lymphodepletion and high-dose IL-2 maintenance
Solution Approach 2:
The engineered TILs are designed to be self-service by autonomously producing cytokines (such as IL-15, IL-7, IL-21) and anti-apoptotic factors (such as Bcl-2) through the delivered mRNA. This self-sufficiency allows the TILs to maintain their own proliferation and survival without requiring external cytokine support, simplifying the treatment protocol
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
Enhanced TILs exhibit increased proliferation, viability, and tumor cell killing without exogenous cytokines, enabling broader patient populations and potential for repeat dosing and concurrent therapies.
Implementation Method 1
passing a cell suspension comprising input TILs through a cell-deforming constriction, thereby causing perturbations of the input TILs
Data Source
AI summary
The present application provides TILs comprising agents that enhance activity and/or proliferative capacity of the TILs, methods of manufacturing such TILs, and methods of using such modified TILs for enhancing an immune response.