TIL Expansion via Transcription Factor Reprogramming
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Solution Overview
Problem
Current methods for expanding tumor infiltrating lymphocytes (TILs) for cancer therapy are inefficient and challenging to scale for commercial production and regulatory approval.
Innovation Solution
A method involving transient genetic alteration processes to reprogram TILs, including obtaining TILs from tumors, expanding them in a cell culture medium with IL-2 and OKT-3, and exposing them to transcription factors or molecules to alter tumor antigen expression and increase tumor antigen-specific T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If traditional REP method is used to expand TILs, then large-scale TIL production is achieved, but the process requires large excess of irradiated allogeneic PBMCs as feeder cells and high doses of IL-2, increasing complexity and cost
Solution Approach 1:
The patent extracts and removes the requirement for irradiated allogeneic PBMCs as feeder cells from the TIL expansion process. The modified REP method achieves large-scale TIL production without these feeder cells, thereby simplifying the process and reducing dependency on additional cell sources while maintaining expansion efficiency
Solution Approach 2:
The patent modifies the REP protocol by changing key parameters: reducing IL-2 dosage requirements and eliminating the feeder cell component. These parameter changes allow the process to achieve the same or better TIL expansion outcomes with reduced complexity and lower costs
2Productivity
If TILs are expanded using REP procedure, then 1000-fold expansion is achieved over 14 days, but the process requires high doses of IL-2 and OKT-3 antibody, increasing treatment cost and potential side effects
Solution Approach 1:
The patent applies parameter changes by optimizing the REP protocol to reduce IL-2 dosage requirements. Through modified culture conditions and timing, the process achieves 1000-fold TIL expansion with lower IL-2 concentrations, thereby reducing treatment costs and minimizing IL-2-related side effects while maintaining high productivity
3Quantity of substance
If conventional TIL expansion methods are used, then therapeutic populations can be produced, but the methods are challenging to scale for commercial production and regulatory approval
Solution Approach 1:
The patent segments the TIL production process into standardized, modular steps that can be independently optimized and controlled. This segmentation facilitates scale-up for commercial production by allowing each stage to be independently validated and controlled, meeting regulatory requirements while maintaining productivity
Solution Approach 2:
The patent implements parameter changes that standardize the expansion process, making it more suitable for commercial manufacturing. By optimizing and fixing key parameters (temperature, IL-2 concentration, culture duration), the process becomes more predictable and scalable, facilitating regulatory approval and consistent commercial production
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
This method enables the production of therapeutic populations of TILs with enhanced efficacy, facilitating commercial-scale manufacturing and regulatory approval for use in human patients.
Implementation Method 1
exposing the second and/or third population of TILs to transcription factors (TFs) and/or other molecules capable of transiently altering protein expression
Implementation Method 2
performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2, and optionally OKT-3
Data Source
AI summary
The present invention provides improved and/or shortened processes and methods for reprogramming TILs in order to prepare therapeutic populations of TILs with increased therapeutic efficacy. Such reprogrammed TILs find use in therapeutic treatment regimens.