Closed TIL Expansion and Gene Editing for Sterile Cell Manufacturing
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current TIL manufacturing processes are limited by length, cost, sterility concerns, and regulatory issues, hindering commercialization and requiring large excess of feeder cells and high doses of IL-2, with a need for more effective TIL therapies that increase patient response rate and robustness.
Innovation Solution
A closed system process for expanding TILs involving multiple expansions with IL-2 and antigen-presenting cells, followed by gene-editing to enhance therapeutic efficacy, with steps performed without opening the system to minimize contamination, and cryopreservation for storage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional open TIL expansion processes are used, then TILs can be expanded, but contamination risk increases and sterility cannot be ensured
Solution Approach 1:
A closed system with integrated gas-permeable surfaces acts as an intermediary between the TIL expansion process and the external environment, allowing gas exchange while preventing contamination. The system includes a culture chamber with gas-permeable bottom and wall surfaces that enable oxygen and carbon dioxide exchange without requiring opening the system to external air.
Solution Approach 2:
The harmful element (contamination risk) is extracted from the system by removing the need to open the culture chamber during the expansion process. The closed system design eliminates exposure to external contaminants while maintaining necessary gas exchange through the gas-permeable surfaces.
2Productivity
If large excess of feeder cells and high doses of IL-2 are used in traditional REP, then TIL expansion is achieved, but cost and complexity increase
Solution Approach 1:
The tumor fragments themselves serve as the feeder cells, eliminating the need for large excess of external feeder cells. The TILs expand by interacting with their own tumor fragments in the closed system, making the process self-sufficient and reducing external inputs.
Solution Approach 2:
The system changes the parameters of the expansion environment by controlling gas composition through the gas-permeable surfaces, optimizing oxygen and carbon dioxide levels to enhance TIL expansion efficiency without requiring excessive feeder cells or high IL-2 doses.
3Reliability
If traditional open expansion processes are used, then TILs can be cultured, but contamination risk and sterility concerns increase
Solution Approach 1:
The gas-permeable surfaces act as an intermediary that allows necessary gas exchange while blocking contamination. The closed system design with integrated gas exchange surfaces simplifies manufacturing by eliminating the need for sterile technique maintenance during the expansion process.
4Ease of operation
If the system is opened during expansion steps, then access for manipulation is achieved, but contamination risk increases
Solution Approach 1:
The harmful factor (contamination risk) is extracted by eliminating the need to open the system. The gas-permeable surfaces provide the necessary gas exchange function without requiring system opening, thereby removing the contamination pathway.
Solution Approach 2:
The gas-permeable surfaces perform multiple functions: they allow gas exchange, maintain closed system sterility, and eliminate the need for opening the system during manipulation. This multi-functionality resolves the contradiction between access and contamination control.
Data Source
AI summary
The present invention provides improved and/or shortened methods for expanding TILs and producing therapeutic populations of TILs, including novel methods for expanding TIL populations in a closed system that lead to improved efficacy, improved phenotype, and increased metabolic health of the TILs in a shorter time period, while allowing for reduced microbial contamination as well as decreased costs. The methods may comprise gene-editing at least a portion of the TILs to enhance their therapeutic efficacy. Such TILs find use in therapeutic treatment regimens.