Modified T Cells Expressing PDE Resist Immunosuppression

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Solution Overview

Problem

The immunosuppressive tumor microenvironment, characterized by high levels of adenosine and prostaglandin E2, inhibits the effectiveness of T cell-based immunotherapies for cancer treatment, limiting their ability to target and destroy cancer cells.

Innovation Solution

Modifying T cells to express a recombinant cAMP phosphodiesterase (PDE) or its fragment, which inhibits cAMP signaling, thereby enhancing their resistance to immunosuppressive factors and increasing their cytotoxicity and cytokine release capabilities, allowing them to more effectively target cancer cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If T cells are used for cancer immunotherapy, then they can target and attack cancer cells, but their effectiveness is inhibited by the immunosuppressive tumor microenvironment containing high levels of adenosine and prostaglandin E2

Engineering Contradiction:

Improveeffectiveness of T cell-based immunotherapyVSAvoidimmunosuppressive effects of adenosine and prostaglandin E2

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful immunosuppressive effects of adenosine and prostaglandin E2 into beneficial effects by engineering T cells to express PDE enzymes. These PDE enzymes specifically degrade cAMP, the second messenger molecule through which adenosine and prostaglandin E2 exert their suppressive effects. By converting the harmful signaling pathway into a targeted degradation mechanism, the modified T cells gain resistance to immunosuppression while maintaining their anti-tumor cytotoxicity

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent changes the biochemical parameter of intracellular cAMP levels within T cells by introducing PDE expression. This parameter change directly counteracts the immunosuppressive signaling caused by adenosine and prostaglandin E2, which act through cAMP elevation. The modified T cells maintain lower intracellular cAMP levels even in the presence of high extracellular adenosine and prostaglandin E2, thereby preserving their functional activity

Inventive Principle:

Principle #35Parameter changes

2Reliability

If T cells are modified to express recombinant cAMP phosphodiesterase, then their resistance to immunosuppressive agents increases, but the complexity of cell modification increases

Engineering Contradiction:

Improveresistance to immunosuppressive agentsVSAvoidcomplexity of T cell modification

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent uses viral vectors as intermediary carriers to deliver the PDE gene into T cells. This intermediary approach simplifies the modification process compared to direct gene editing methods, as viral transduction is a well-established, relatively simple procedure. The viral vector acts as a mediator that efficiently transfers the genetic material into the T cells, enabling PDE expression without requiring complex genomic manipulation

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs a universal approach by using PDE enzymes that can counteract multiple immunosuppressive agents simultaneously. A single PDE expression construct provides resistance against both adenosine and prostaglandin E2, as both agents exert their effects through the cAMP pathway. This multi-functional benefit reduces the complexity that would otherwise arise from needing separate modification strategies for each immunosuppressive agent

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 modified T cells demonstrate increased resistance to immunosuppressive agents and improved cytotoxicity and cytokine release, enhancing their ability to induce apoptosis in cancer cells and overcome inhibitory effects, making them more effective in cancer immunotherapy.

Implementation Method 1

a cAMP phosphodiesterase (PDE) or a fragment thereof, which reduces cAMP signalling

Methodology Applied

Scientific EffectPhosphodiesterase (PDE) enzyme activity: Enzyme

Data Source

PatentUS10689620B2T cells with increased immunosuppression resistance

Publication Date: 2020.06.23 ADAPTIMMUNE

AI summary

This invention relates to the treatment of cancer in an individual by administration of a population of modified T cells that express a recombinant cAMP phosphodiesterase (PDE) or a fragment thereof and an antigen receptor which binds specifically to cancer cells in the individual. Populations of modified T cells and methods of producing populations of modified T cells are provided, along with pharmaceutical compositions and methods of treatment.