TIL Expansion via PD-1 Knockdown and Anti-CD3 Activation
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Solution Overview
Problem
Current TIL manufacturing and treatment processes are limited by length, cost, and sterility concerns, particularly for patients refractory to checkpoint inhibitor therapies, necessitating a more efficient method for generating therapeutic TILs.
Innovation Solution
A method involving obtaining TILs from tumor tissue, expanding them using IL-2 and activation with anti-CD3 agonist beads, followed by gene-editing and further expansion with antigen-presenting cells and IL-2, to produce a therapeutic population of TILs within a shortened timeframe.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional TIL expansion methods are used, then therapeutic TILs can be produced, but the manufacturing process is lengthy and costly
Solution Approach 1:
The patent applies preliminary action by pre-activating TILs with anti-CD3/anti-CD28 beads before expansion, and by pre-preparing optimized culture media with specific cytokine combinations. This preliminary preparation enables faster subsequent expansion phases, reducing overall manufacturing time while maintaining therapeutic efficacy
Solution Approach 2:
The patent implements parameter changes by optimizing culture conditions including specific cytokine concentrations (IL-2, IL-7, IL-15), culture medium compositions, and activation protocols. These parameter optimizations enable accelerated TIL expansion rates while preserving cell functionality and reducing total manufacturing duration
2Productivity
If traditional TIL expansion methods are used, then therapeutic TILs can be produced, but the process is expensive
Solution Approach 1:
The patent applies self-service by engineering TILs with autonomous cytokine production capabilities through genetic modification. The modified TILs produce their own growth factors and survival signals, eliminating the need for continuous exogenous cytokine supplementation and reducing media costs throughout the expansion process
Solution Approach 2:
The patent reduces manufacturing costs by optimizing expansion parameters to achieve higher expansion fold-squares with reduced cell input requirements. By changing culture conditions and activation protocols, the process achieves therapeutic output with less starting material and reduced resource consumption
3Productivity
If traditional TIL expansion methods are used, then therapeutic TILs can be produced, but sterility concerns arise during extended manufacturing
Solution Approach 1:
The patent applies skipping by implementing accelerated expansion protocols that rapidly produce therapeutic TILs in compressed timeframes. By rushing through the manufacturing process with optimized activation and expansion phases, the total duration is reduced from weeks to days, minimizing the window for contamination while achieving sufficient expansion
Solution Approach 2:
The patent implements preliminary action by establishing sterile conditions and activation protocols before expansion begins. Pre-activated TILs in controlled sterile environments with pre-prepared culture conditions reduce the need for prolonged manufacturing processes, thereby reducing sterility maintenance requirements
Data Source
AI summary
The present invention provides improved methods for expanding TILs and producing therapeutic populations of TILs, including methods for gene-editing at least a portion of the TILs to enhance their therapeutic efficacy. The methods lead to improved efficacy, improved phenotype, and increased metabolic health of the TILs in a shorter time period, while allowing for reduced microbial contamination as well as decreased costs. Such TILs find use in therapeutic treatment regimens.