TIL Expansion Using Closed-System Bioreactors for Melanoma Therapy

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Solution Overview

Problem

Current treatments for melanoma, particularly in patients refractory to BRAF and MEK inhibitor treatments, lack effective options due to limitations in TIL manufacturing processes and therapies, leading to a need for a more efficient method to generate and administer tumor-infiltrating lymphocytes (TILs).

Innovation Solution

A method involving the expansion of TILs using a closed system with IL-2, OKT-3, and antigen-presenting cells, followed by cryopreservation and administration with BRAF and/or MEK inhibitors, to treat cancer patients, including those with V600 mutations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If traditional TIL manufacturing processes are used, then the manufacturing process is simple, but the number of TILs produced is insufficient for therapeutic administration

Engineering Contradiction:

Improvenumber of TILsVSAvoidmanufacturing process complexity

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The manufacturing process is divided into multiple sequential expansion stages (e.g., initial expansion, rapid expansion, and consolidation phases), each occurring in separate bioreactors or culture vessels. This segmentation allows each stage to be optimized independently for maximizing TIL yield while maintaining process control and quality standards.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs nested expansion strategies where TILs are expanded in multiple tiers of bioreactors with varying capacities. Smaller culture vessels are used in early stages, then progressively larger bioreactors are engaged as the TIL population grows, creating a nested production architecture that scales efficiently to generate therapeutic doses.

Inventive Principle:

Principle #7Nested doll (Nesting)

2Reliability

If TIL expansion is performed using open systems, then the process is easier to operate, but contamination risk increases

Engineering Contradiction:

Improvecontamination-free productionVSAvoidprocess operation difficulty

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent introduces automated liquid handling systems, closed-connecting manifolds, and sterile filtration units as intermediary devices between operators and the TIL culture system. These intermediaries enable process adjustments, media changes, and cell harvesting without breaking sterile barriers, thus maintaining contamination-free production while simplifying operator interactions.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

Manual mechanical operations (open system access, manual media addition, manual harvesting) are replaced with automated robotic systems and closed-loop fluid handling mechanisms. This substitution eliminates the need to open sterile systems during operations, ensuring reliability while reducing operational complexity through automation.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Reliability

If TIL therapy is administered alone, then the treatment approach is simple, but efficacy is limited for refractory patients

Engineering Contradiction:

Improvetreatment efficacyVSAvoidtreatment regimen complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent combines TIL therapy with BRAF inhibitors and/or MEK inhibitors in an integrated treatment regimen. The biological mechanisms of TILs (direct tumor cell lysis and immune activation) are merged with the molecular targeting mechanisms of BRAF/MEK inhibitors (blocking oncogenic signaling pathways), creating a synergistic effect that overcomes resistance mechanisms in refractory melanoma patients.

Inventive Principle:

Principle #5Merging (Combining)

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 method significantly increases the number of TILs, enabling a therapeutic population that can be effectively administered to patients, potentially improving treatment outcomes for melanoma patients resistant to standard therapies.

Implementation Method 1

performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs

Methodology Applied

Scientific EffectCytokine stimulation:

Implementation Method 2

performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs)

Methodology Applied

Scientific EffectAntibody-antigen binding:

Implementation Method 3

cryopreserving the infusion bag comprising the harvested TIL population from step (f) using a cryopreservation process

Methodology Applied

Scientific EffectCryopreservation:

Data Source

PatentUS20240131064A1Treatment of cancer patients with tumor infiltrating lymphocyte therapies in combination with BRAF inhibitors and/or MEK inhibitors

Publication Date: 2024.04.25 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 cancer with a V600 mutation with TILs as described herein in combination with BRAF inhibitors and/or MEK inhibitors.