TIL Preselection Using Immune Checkpoint Markers
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Solution Overview
Problem
Current methods for expanding tumor-infiltrating lymphocytes (TILs) for cancer therapy are limited by length, cost, and sterility concerns, and lack efficient processes for commercial-scale manufacturing and regulatory approval, particularly in selecting TILs with enhanced tumor-specific killing capacity.
Innovation Solution
A method involving preselection of TILs based on PD-1, CD39, CD38, CD103, CD101, LAG3, TIM3, and/or TIGIT expression, followed by a two-step expansion process using IL-2 and OKT-3 in the presence of antigen-presenting cells, to produce a therapeutic population of TILs with enhanced cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional TIL expansion methods are used, then TILs can be expanded for therapy, but the process is time-consuming and costly with sterility concerns
Solution Approach 1:
The patent applies preliminary action by pre-selecting TILs based on PD-1, CD39, CD38, CD103, CD101, LAG3, TIM3, and/or TIGIT expression before expansion. This pre-selection step identifies and enriches for tumor-reactive TILs with enhanced cytotoxicity, allowing the subsequent expansion to proceed more efficiently with fewer cells and reduced time requirements compared to conventional methods that expand all TILs without selection.
2Ease of manufacture
If conventional TIL expansion methods are used, then TILs can be produced for therapy, but the process is complex and difficult to scale for commercial manufacturing
Solution Approach 1:
The patent applies parameter changes by establishing specific expression thresholds and markers (PD-1, CD39, CD38, CD103, CD101, LAG3, TIM3, TIGIT) to define and select tumor-reactive TILs. By changing the selection parameters to focus on these specific markers, the process becomes more standardized and reproducible, facilitating commercial-scale manufacturing and regulatory approval while reducing overall process complexity through clear selection criteria.
3Reliability
If conventional TIL expansion methods are used, then TILs can be expanded, but sterility concerns limit commercialization
Solution Approach 1:
The patent applies the extraction principle by isolating and selecting specific TIL subsets based on their marker expression (PD-1, CD39, CD38, CD103, CD101, LAG3, TIM3, TIGIT) before expansion. This extraction of tumor-reactive TILs with specific phenotypes allows for a more controlled and reliable expansion process that maintains sterility better, as the selected cells are already enriched for therapeutic relevance, reducing the need for extensive post-expansion processing and enhancing commercialization potential.
4Manufacturing precision
If TILs are expanded without preselection, then the process is simpler, but the tumor-specific killing capacity is reduced
Solution Approach 1:
The patent applies preliminary action by performing marker-based selection (PD-1, CD39, CD38, CD103, CD101, LAG3, TIM3, TIGIT) before expansion to enrich for tumor-reactive TILs. This pre-selection step ensures that the subsequent expansion produces TILs with enhanced tumor-specific killing capacity and higher therapeutic relevance, while the selection process itself can be integrated into existing manufacturing workflows to maintain simplicity.
Data Source
AI summary
The present invention provides methods for preselecting TILs based on PD-1, CD39, CD38, CD103, CD101, LAG3, TIM3 and/or TIGIT expression, as well as methods for expanding those preselected PD-1, CD39, CD38, CD103, CD101, LAG3, TIM3 and/or TIGIT positive TILs in order to produce therapeutic populations of TILs with enhanced tumor-specific killing capacity (e.g., enhanced cytotoxicity).