TIL Expansion via CD39/CD69 Selection and Knockout
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Solution Overview
Problem
Current TIL manufacturing and treatment processes are limited by length, cost, and sterility concerns, severely restricting their use for patients refractory to other checkpoint inhibitor therapies, necessitating a more efficient method for generating therapeutic TILs.
Innovation Solution
A shortened process for preparing TILs involving CD39/CD69 preselection, knockout, or combination thereof, through genetic modification, along with expansion methods using IL-2, OKT-3, and antigen presenting cells, and cryopreservation for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional TIL expansion methods are used, then therapeutic efficacy is achieved, but manufacturing time and cost increase
Solution Approach 1:
The patent applies preliminary action by performing CD39/CD69 selection and genetic modification (knockout) of TILs before the expansion phase. This pre-processing step identifies and prepares the most promising TIL subset in advance, allowing the subsequent expansion to proceed more efficiently with fewer steps and reduced time while maintaining high therapeutic efficacy.
Solution Approach 2:
The patent changes critical parameters of the TIL population by selecting for CD39LO/CD69LO phenotype and inducing genetic modification (knockout) of specific genes. These parameter changes in cell surface markers and genetic composition enable the TILs to expand more rapidly and effectively, resolving the contradiction between manufacturing time and therapeutic efficacy.
2Ease of manufacture
If conventional TIL manufacturing processes are used, then therapeutic TILs are produced, but sterility concerns and cost limitations arise
Solution Approach 1:
The patent segments the TIL manufacturing process into distinct modular steps: (1) TIL isolation, (2) CD39/CD69 selection, (3) genetic modification (knockout), and (4) expansion. This segmentation allows each step to be optimized independently for both ease of manufacture and sterility control, with critical sterility-critical steps being clearly defined and controlled.
Solution Approach 2:
The patent uses CD39/CD69 selection as an intermediary step that bridges the isolation and expansion phases. This selection mechanism serves as a mediator to identify and prepare the optimal TIL subset before expansion, simplifying the overall manufacturing process while ensuring sterility through controlled selection procedures.
3Loss of time
If TILs are expanded rapidly, then manufacturing time is reduced, but control over cell population characteristics becomes more difficult
Solution Approach 1:
The patent performs preliminary selection for CD39LO/CD69LO phenotype and genetic modification before expansion. This pre-characterization ensures that the TIL population entering expansion has defined and controlled characteristics, allowing rapid expansion to proceed while maintaining precision over the final cell population's therapeutic properties.
Solution Approach 2:
By inducing specific genetic modifications (knockout) and selecting for specific phenotypic parameters (CD39LO/CD69LO) before expansion, the patent establishes controlled starting conditions. This allows the expansion to proceed rapidly without losing control over the final cell population's critical therapeutic characteristics.
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 approach enables the production of therapeutic TIL populations with increased efficacy for cancer treatment, addressing the limitations of existing methods by reducing manufacturing time and costs while ensuring sterility and enhanced therapeutic effectiveness.
Implementation Method 1
performing an initial expansion by culturing the first population of TILs in a first cell culture medium comprising IL-2, OKT-3, and antigen presenting cells (APCs)
Implementation Method 2
cryopreserving the infusion bag comprising the harvested TIL population from step (g) using a cryopreservation process
Data Source
AI summary
Provided herein are TILs that are (i) CD39LO/CD69LO and/or CD39/CD69 double negative, (ii) CD39/CD69 double knock-out, or (iii) the combination of (i) and (ii). In some embodiments, the subject TILs are produced by genetically manipulating a population of TILs that have been selected for (i) CD39LO/CD69LO and/or CD39/CD69 double negative, (ii) CD39/CD69 double knock-out, or (iii) the combination of (i) and (ii) expression (e.g, a (i) CD39LO/CD69LO and/or CD39/CD69 double negative, (ii) CD39/CD69 double knock-out, or (iii) the combination of (i) and (ii) enriched TIL population). Also provided herein are expansion methods for producing such genetically modified TILs and methods of treatment using such TILs.