Tumor Infiltrating Lymphocyte Isolation via Semi-Automatic Disaggregation
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Solution Overview
Problem
Current methods for isolating and expanding tumor-infiltrating lymphocytes (TILs) from resected tumors are labor-intensive, require strict aseptic conditions, and often result in cell deterioration due to oxygen deficiency, leading to suboptimal viability and diversity of the final cellular product.
Innovation Solution
A semi-automatic aseptic tissue processing method and device that disaggregates tumors using repeated physical pressure in the presence of enzyme solution, followed by cryopreservation and subsequent expansions with IL-2 and OKT-3, to produce a therapeutic population of TILs, while maintaining a closed system to minimize contamination and cell damage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If manual isolation and expansion methods are used, then flexibility and adaptability are maintained, but labor intensity increases and processing efficiency decreases
Solution Approach 1:
The system is divided into distinct functional modules: a disaggregation module for mechanical tissue breakdown, an enrichment module for cell separation, and a stabilization module for cell preservation. Each module performs a specific function, allowing automated high-throughput processing while maintaining manageable system complexity through functional segmentation.
Solution Approach 2:
A closed-system processing device acts as an intermediary between the resected tumor and the final TIL product. This intermediary system automates the isolation and expansion processes, reducing manual labor while maintaining controlled conditions necessary for cell viability.
2Reliability
If strict aseptic conditions are maintained, then contamination is prevented, but processing time and operational complexity increase
Solution Approach 1:
The system performs preliminary aseptic preparation by maintaining a closed-system environment throughout the entire processing workflow. Media and reagents are pre-sterilized and introduced through sealed interfaces, eliminating the need for time-consuming aseptic technique adjustments during processing and reducing overall processing time while ensuring contamination prevention.
Solution Approach 2:
The closed-system processing device creates a controlled, sterile environment that acts as a protective barrier against contamination. This inert environment allows faster processing compared to traditional open-system aseptic techniques, as continuous monitoring and control eliminate the need for prolonged manual sterile handling.
3Quantity of substance
If tumors are disaggregated using traditional methods, then cell recovery is achieved, but cell deterioration occurs due to oxygen deficiency
Solution Approach 1:
The disaggregation module applies periodic mechanical action to break down tumor tissue into smaller fragments. This periodic disaggregation, combined with controlled media flow, ensures adequate oxygen supply to cells throughout the process, preventing hypoxic deterioration while maximizing cell recovery. The cyclic nature of the disaggregation allows fresh media to continuously reach embedded cells.
Solution Approach 2:
Traditional enzymatic or manual disaggregation methods are replaced with a mechanical disaggregation system that applies controlled physical forces. This mechanical approach, combined with a closed-system design that maintains oxygen levels, achieves efficient tissue breakdown while preventing the oxygen deficiency-induced cell deterioration associated with traditional methods.
4Reliability
If open-system processing is used, then ease of operation is maintained, but contamination risk and cell damage increase
Solution Approach 1:
Multiple functions (disaggregation, enrichment, stabilization) are merged into a single integrated closed-system processing device. This integration maintains operational simplicity by providing a unified, automated workflow while simultaneously protecting cells from contamination and damage through the closed-system environment. The merged system eliminates the need for transferring cells between separate open containers.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This method enhances the viability and diversity of TIL populations, allowing for effective cryopreservation and expansion, thereby improving the potency and therapeutic potential of TILs for cancer treatment.
Implementation Method 1
disaggregating the tumor by automatically executing one or more tissue processing steps... the disaggregation comprises repeated physical pressure applied 120 to 360 times per minute at up to 6 N/cm2
Implementation Method 2
disaggregating the tumor by automatically executing one or more tissue processing steps... in the presence of a media enzyme solution
Implementation Method 3
cryopreserving the disaggregated tumor... storing the cryopreserved disaggregated tumor product in a frozen state
Data Source
AI summary
The subject matter described herein is directed to methods for determining the potency of isolated and expanded tumor infiltrating lymphocytes (TILs) and producing therapeutic populations of TILs, and compositions involving the same and methods of treatment involving the same.