Closed-System TIL Manufacturing for Checkpoint-Refractory NSCLC

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Solution Overview

Problem

There is an urgent need for improved therapeutic options for non-small-cell lung cancer (NSCLC) patients who are refractory to anti-PD-1, anti-PD-L1, and/or VEGF inhibitor treatments, as current treatments have limited efficacy and high toxicity, and existing TIL manufacturing processes are lengthy and costly.

Innovation Solution

A shortened method for producing tumor infiltrating lymphocytes (TILs) using a closed system expansion process involving IL-2, OKT-3, and antigen presenting cells, followed by cryopreservation, to treat NSCLC patients with PD-L1 expression <1% or 1%-49% or without driver mutations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional TIL manufacturing processes are used, then therapeutic efficacy is achieved, but treatment time is excessive and cost is high

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtreatment time

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent divides the TIL manufacturing process into distinct modular stages: initial expansion, rapid expansion, and consolidation. Each stage uses optimized culture conditions and can be performed in separate bioreactors, allowing parallel processing and reducing overall manufacturing time while maintaining therapeutic efficacy.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent performs preliminary selection and expansion of TILs before final therapy administration. By pre-expanding TILs in controlled conditions and selecting for desired phenotypes beforehand, the process reduces the time needed for later manufacturing steps and ensures therapeutic potency is achieved earlier in the workflow.

Inventive Principle:

Principle #10Preliminary action

2Reliability

If traditional TIL manufacturing processes are used, then therapeutic efficacy is achieved, but manufacturing cost is excessive

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmanufacturing cost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent develops universal culture media formulations and expansion protocols that can be applied across different TIL manufacturing scales and patient cases. This multi-functionality reduces the need for specialized, expensive reagents and equipment for each individual treatment, thereby lowering overall manufacturing costs while maintaining efficacy.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent optimizes culture conditions by adjusting parameters such as cytokine concentrations, cell density, and incubation times to achieve maximum TIL expansion efficiency. By finding optimal parameter ranges, the process reduces waste of expensive reagents and minimizes the duration of costly manufacturing steps.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If checkpoint inhibitors are used for NSCLC treatment, then response rate is improved, but toxicity increases and resistance develops

Engineering Contradiction:

Improveresponse rateVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses TILs as an intermediary between the patient's immune system and the tumor. Rather than relying solely on checkpoint inhibitors that block immune checkpoints systemically, TILs provide targeted immunotherapy where expanded tumor-specific lymphocytes are infused to directly attack the tumor, reducing systemic toxicity while maintaining anti-tumor efficacy.

Inventive Principle:

Principle #24Intermediary (Mediator)

4Reliability

If checkpoint inhibitors are used for NSCLC treatment, then response rate is improved, but treatment durability decreases

Engineering Contradiction:

Improveresponse rateVSAvoidtreatment durability

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent performs preliminary expansion and selection of TILs to ensure they possess optimal anti-tumor activity and persistence characteristics before infusion. By pre-selecting for desired phenotypes and functional properties, the infused TILs are better equipped to provide durable, long-lasting anti-tumor responses compared to standard checkpoint inhibitor therapy alone.

Inventive Principle:

Principle #10Preliminary action

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

The method significantly expands TIL populations, providing a therapeutically effective treatment for NSCLC patients refractory to checkpoint inhibitors, with improved response rates and reduced toxicity.

Implementation Method 1

antigen presenting cells

Methodology Applied

Scientific EffectAntigen presentation:

Implementation Method 2

IL-2, OKT-3

Methodology Applied

Scientific EffectCytokine stimulation:

Implementation Method 3

closed system expansion process

Methodology Applied

Scientific EffectPhysical containment: Physical Containment

Implementation Method 4

followed by cryopreservation

Methodology Applied

Scientific EffectCryopreservation: Cryogenics

Data Source

PatentUS12553029B2Treatment of NSCLC patients with tumor infiltrating lymphocyte therapies

Publication Date: 2026.02.17 IOVANCE BIOTHERAPEUTICS INC

AI summary

The present invention provides improved and/or shortened processes and methods for preparing TILs in order to prepare therapeutic populations of TILs with increased therapeutic efficacy for the treatment of non-small cell lung carcinoma (NSCLC), wherein the NSCLC is refractory to treatment with an anti-PD-1 antibody and/or anti-PD-L1 antibody and/or VEGF inhibitor, or wherein the NSCLC has a predetermined tumor proportion score (TPS).