PD-1 Positive TIL Selection for Enhanced Expansion Yield
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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 the preselection of PD-1 positive TILs, followed by a priming expansion using IL-2, OKT-3, and antigen-presenting cells (APCs) in a gas-permeable container, and a rapid second expansion with increased APCs, to produce a therapeutic population of TILs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional TIL expansion methods are used, then TILs can be expanded, but the process is time-consuming and costly
Solution Approach 1:
The patent applies preliminary action by performing PD-1 positive selection of TILs before expansion. This preselection step enriches for tumor-reactive cells with enhanced killing capacity, allowing the subsequent expansion to proceed more efficiently and produce therapeutically effective dosages faster and with lower cost
2Productivity
If conventional TIL expansion methods are used, then TILs can be expanded, but sterility concerns arise
Solution Approach 1:
The patent segments the TIL expansion process into distinct phases: initial PD-1 positive selection, priming expansion phase, and rapid expansion phase. This segmentation allows each phase to be optimized independently for both efficiency and sterility control, with the priming phase establishing controlled growth conditions before the rapid expansion phase
3Reliability
If PD-1 positive TILs are selected and expanded, then tumor-specific killing capacity is enhanced, but the process complexity increases
Solution Approach 1:
The patent applies parameter changes by using PD-1 expression level as a selection criterion to identify and enrich for tumor-reactive TILs. This parameter-based selection (PD-1 positivity) simplifies the complex task of identifying effective tumor-fighting cells, enabling enhanced tumor-specific killing capacity through a manageable selection and expansion process
4Productivity
If large excess of irradiated allogeneic PBMCs is used, then TIL expansion is achieved, but cost and resource requirements increase
Solution Approach 1:
The patent extracts and utilizes the enhanced tumor-reactive potential from PD-1 positive TILs through preselection. By concentrating on this specialized subset of TILs with inherent tumor-killing capacity, the method reduces dependence on large quantities of feeder cells, achieving high expansion yields with fewer resources
Data Source
AI summary
The present invention provides methods for preselecting TILs based on PD-1 expression, as well as methods for expanding those preselected PD-1 positive TILs in order to produce therapeutic populations of TILs with enhanced tumor-specific killing capacity (e.g., enhanced cytotoxicity).