TIL Culture Oxygen Switching for Trm Cell Expansion
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Solution Overview
Problem
Existing treatments for cancer using tumor-infiltrating lymphocytes (TIL) face challenges in expanding high numbers of tumor-reactive TILs, leading to resistance and poor prognosis, necessitating new models and strategies for improving TIL therapy.
Innovation Solution
A method involving culturing TILs in varying oxygen environments, including normoxic and hypoxic conditions, with specific protocols using IL-2, anti-CD3 antibody, and allogeneic feeder cells, to expand TILs and increase the number of Tumor-Resident Memory (Trm) cells, combined with the use of antibodies like anti-PD1, anti-CTLA4, and anti-TIM-3 to enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If TILs are cultured in normoxic conditions during pre-REP and REP phases, then TIL expansion is achieved, but the number of Trm cells is insufficient
Solution Approach 1:
The patent applies parameter changes by switching oxygen concentration from normoxic (20-22%) during pre-REP to hypoxic (0-19.99%, preferably 1-5%) during REP phase. This parameter change optimizes the differentiation of TILs into Trm cells while maintaining expansion efficiency, resolving the contradiction between quantity of Trm cells and productivity of TIL expansion.
2Quantity of substance
If TILs are cultured in hypoxic conditions during pre-REP phase, then Trm cell differentiation is enhanced, but TIL expansion is inhibited
Solution Approach 1:
The patent segments the TIL culture process into two distinct phases: pre-REP phase (normoxic conditions for expansion) and REP phase (hypoxic conditions for Trm differentiation). This segmentation allows each phase to operate under optimal conditions, resolving the contradiction between Trm cell differentiation and TIL expansion efficiency.
Solution Approach 2:
The patent implements dynamic adjustment of oxygen concentration based on the specific needs of each culture phase. The system transitions from static normoxic conditions to dynamic hypoxic conditions during REP phase, optimizing both Trm differentiation and expansion efficiency at different time points.
3Quantity of substance
If standard TIL expansion protocols are used, then TIL numbers are increased, but tumor reactivity and therapeutic efficacy are reduced
Solution Approach 1:
The patent changes the oxygen parameter from standard normoxic conditions to hypoxic conditions (1-5%) during the REP phase. This parameter change enhances tumor reactivity and therapeutic efficacy while maintaining TIL expansion, resolving the contradiction between quantity of TILs and reliability of tumor reactivity.
Solution Approach 2:
The patent creates a simplified mouse model system that copies and adapts human TIL therapy principles to pre-clinical settings. This model enables optimization of culture conditions (including hypoxic REP phase) to enhance tumor reactivity while maintaining expandability, resolving the contradiction between TIL numbers and therapeutic efficacy.
Data Source
AI summary
Disclosed are methods for expanding tumor infiltrating lymphocytes (TILs) and driving TILs towards a memory T cell phenotype. Also disclosed is the creation of a mouse model to investigate adoptive cell therapy using TILs.