Gene-edited TIL Expansion in Closed Systems
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Solution Overview
Problem
Current methods for expanding tumor-infiltrating lymphocytes (TILs) for cancer therapy are limited by technical, logistical, and regulatory issues, particularly in achieving scalable and sterile commercial production, and there is a need for more effective therapies to increase patient response rates and robustness.
Innovation Solution
A method for expanding TILs involves processing tumor fragments in a closed system with IL-2 and OKT-3, followed by antigen-presenting cells, and includes gene-editing to enhance therapeutic efficacy, with cryopreservation for therapeutic dosages, utilizing closed systems to minimize contamination and maximize yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional open TIL expansion methods are used, then the process is simple to operate, but contamination risk increases and sterility cannot be ensured
Solution Approach 1:
The patent employs a closed system that maintains a sterile environment throughout the TIL expansion process. The system includes a culture vessel with a sealed lid, where all operations occur without exposure to external contamination. This closed environment acts as an inert atmosphere that prevents microbial contamination while maintaining cell viability, thus ensuring sterility without significantly complicating the operational process.
2Productivity
If rapid expansion protocol (REP) is used to achieve 1000-fold expansion, then TIL yield increases, but the process requires large excess of feeder cells and multiple donors
Solution Approach 1:
The patent extracts and eliminates the requirement for large numbers of irradiated allogeneic PBMC feeder cells from the TIL expansion process. By using a closed system with optimized culture conditions including specific cytokine combinations (IL-2, IL-15, IL-21) and antigen-presenting cells, the method achieves high-level TIL expansion without the complex logistics of coordinating multiple blood donors and processing large quantities of feeder cells.
Solution Approach 2:
The patent changes the cultural parameters of TIL expansion by using a closed system with controlled atmosphere, optimized cytokine concentrations, and specific CO2 levels. These parameter changes enable high-efficiency expansion (achieving significant fold-expansion) while simplifying the overall process by eliminating the need for feeder cells and reducing the number of operational steps required.
3Reliability
If gene-editing is performed on TILs to enhance therapeutic effect, then treatment efficacy improves, but manufacturing time and process complexity increase
Solution Approach 1:
The patent performs gene-editing modifications on TILs during the expansion process itself, rather than as a separate post-expansion step. By integrating the gene-editing procedure into the existing closed-system expansion workflow, the method enhances therapeutic efficacy through genetic modification while minimizing additional time loss. The TILs are modified in situ during culture, allowing parallel processing of expansion and genetic enhancement.
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.