Closed-System TIL Expansion for Sterile Rapid Cell Manufacturing
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current TIL manufacturing processes are limited by length, cost, sterility concerns, and regulatory issues, hindering their commercialization and widespread use in human patients.
Innovation Solution
A closed-system method for expanding TILs involving multiple expansions with IL-2, OKT-3, and antigen-presenting cells, followed by cryopreservation, to produce a therapeutic population of TILs efficiently and reliably.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If traditional open-system TIL expansion methods are used, then TIL yield can be increased, but microbial contamination risk increases and sterility is compromised
Solution Approach 1:
The patent employs a closed-system culture method that creates a sterile, controlled environment for TIL expansion. The system uses sterile filters, closed culture vessels, and controlled atmosphere conditions to prevent microbial contamination while maintaining high TIL yields. This inert environment approach eliminates the need for open manipulation during the expansion process, thereby preventing contamination without compromising productivity.
Solution Approach 2:
The patent introduces sterile filtration systems and closed-transfer mechanisms as intermediaries between the external environment and the TIL culture system. These intermediaries allow for the addition of nutrients and removal of waste products without compromising sterility, enabling high-yield expansion while maintaining a contamination-free environment.
2Productivity
If rapid expansion protocols are used to increase TIL production speed, then productivity improves, but process complexity and manufacturing challenges increase
Solution Approach 1:
The patent divides the TIL expansion process into distinct phases: initial activation phase, rapid expansion phase, and harvest phase. Each phase has optimized conditions and durations. This segmentation allows the process to achieve rapid expansion (1,000-fold in 14 days) while maintaining manageable complexity through standardized protocols for each stage, facilitating commercial manufacturing.
Solution Approach 2:
The patent systematically varies critical parameters including IL-2 concentration, feeder cell ratios, culture vessel type, and oxygen levels across different expansion phases. These controlled parameter changes enable rapid TIL proliferation while maintaining process consistency and reproducibility, reducing manufacturing complexity despite high productivity requirements.
3Quantity of substance
If large excess of feeder cells and high doses of IL-2 are used to achieve rapid TIL expansion, then TIL yield increases, but manufacturing cost increases
Solution Approach 1:
The patent employs feeder cells that are irradiated and serve as a self-limiting support system. The irradiated feeder cells provide necessary growth factors and surface contact signals for TIL expansion but cannot proliferate themselves, eliminating the need for continuous feeder cell supplementation. This self-service approach reduces the total feeder cell requirement and associated costs while maintaining high TIL yields.
Solution Approach 2:
The patent implements continuous IL-2 supplementation and closed-system culture that maintains optimal growth conditions throughout the expansion period. This continuous action maximizes the efficiency of IL-2 utilization, reducing the total dose required compared to intermittent supplementation methods, thereby lowering manufacturing costs while achieving rapid expansion.
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. Such TILs find use in therapeutic treatment regimens.