Closed-System TIL Expansion With Cryopreservation for Sterile Cell Therapy
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Solution Overview
Problem
Current TIL manufacturing processes are limited by length, cost, sterility concerns, and logistical issues, hindering their commercialization and regulatory approval for 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
1Reliability
If traditional open-system TIL expansion methods are used, then flexibility in process monitoring and adjustment is maintained, but microbial contamination risk increases and sterility concerns worsen
Solution Approach 1:
The patent introduces a closed system as an intermediary environment that isolates the TIL expansion process from external contamination sources. The system includes sealed culture vessels, closed media delivery mechanisms, and automated cell processing equipment that maintains sterility throughout the expansion process without requiring frequent opening or manual intervention.
Solution Approach 2:
The patent employs automated cell processing systems that replicate manual operations in a controlled, sterile environment. Automated cell harvesters, washers, and resuspension devices copy the functions of manual techniques while maintaining closed-system integrity, thereby preventing contamination while achieving the same operational goals.
2Productivity
If rapid expansion protocols are used to increase TIL production speed, then therapeutic dosage is achieved faster, but process complexity and cost increase
Solution Approach 1:
The patent divides the TIL expansion process into distinct phases: initial tumor fragmentation and TIL isolation, intermediate expansion with feeder cells, and final amplification. Each phase is optimized independently with specific culture conditions, cytokine combinations, and feeder cell ratios, allowing rapid overall expansion while maintaining manageable complexity through modular process design.
Solution Approach 2:
The patent systematically varies critical process parameters including IL-2 concentration, feeder cell-to-TIL ratio, culture vessel surface area-to-volume ratio, and oxygen tension to maximize expansion rate at each stage. These parameter optimizations enable accelerated TIL production while the standardized protocols reduce operational complexity through defined operating conditions.
3Quantity of substance
If large volumes of culture media are used to support high-density TIL expansion, then cell growth is maintained, but cost and processing burden increase
Solution Approach 1:
The patent employs culture vessels with optimized surface properties, including coated surfaces and microcarrier beads that provide localized attachment sites for TILs. This allows high cell density in reduced media volumes by concentrating nutrients and growth factors at cell-matrix interfaces, thereby supporting high TIL production with lower overall media consumption and cost.
4Productivity
If multiple donor PBMCs are used as feeder cells to achieve robust TIL expansion, then expansion efficiency improves, but logistical complexity and sterility risks increase
Solution Approach 1:
The patent combines multiple donor PBMCs into a single pooled feeder cell preparation that is processed and quality-tested as one unit. This pooling approach maintains the immunological diversity and expansion efficiency of multiple donors while simplifying logistics, reducing the number of separate sterile manipulations required, and minimizing contamination risk through unified processing and storage.
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.