Isolating Short-Lived Effector T Cells for Infectious Disease Therapy

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Solution Overview

Problem

Current treatments for severe infectious diseases like COVID-19, such as convalescent plasma and monoclonal antibodies, face challenges including limited availability, high costs, and adverse effects like cytokine release syndrome and graft-versus-host disease, highlighting the need for a more effective and safer therapeutic option.

Innovation Solution

The development of a method to produce and isolate short-lived effector T cells (SLECs) specific to disease antigens, characterized by their cytotoxicity and short lifespan, which can be rapidly produced and administered to target and eliminate infected cells without causing rejection reactions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If convalescent plasma is used for treatment, then therapeutic effect is achieved, but availability is limited and neutralizing antibody titers are low

Engineering Contradiction:

Improvetherapeutic effectVSAvoidamount of plasma

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The invention extracts and isolates specific T cell subpopulations (TEMRA and SLEC) from convalescent donor blood, separating them from the bulk plasma and other cellular components. This allows concentration of the therapeutically relevant cells while discarding the majority of plasma volume that limits availability.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention changes the therapeutic parameter from using whole plasma to using purified T cell subpopulations with specific phenotypic markers (CD45RA+, CD45RO-, CD27- for TEMRA; CD45RA+, CD45RO-, CD27+ for SLEC). This parameter change enables higher cell concentration and better therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If monoclonal antibodies are used for treatment, then therapeutic effect is achieved, but cost is very high

Engineering Contradiction:

Improvetherapeutic effectVSAvoidcost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The invention uses autologous or allogeneic T cells that can be generated through standard cell culture techniques rather than requiring expensive monoclonal antibody production facilities. The T cells are produced in bulk and can be frozen for later use, providing a more cost-effective alternative.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The invention creates copies of functional T cells through in vitro expansion and differentiation protocols, allowing unlimited production of therapeutic cells from a single donor without the need for expensive monoclonal antibody synthesis infrastructure.

Inventive Principle:

Principle #26Copying

3Reliability

If CAR/TCR-T therapy is used, then specific recognition and eradication of infected cells is achieved, but complexity of set-up is high and side effects occur

Engineering Contradiction:

Improvespecific recognitionVSAvoidcomplexity of set-up

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

Instead of modifying patient T cells with complex CAR/TCR constructs (the conventional approach), the invention uses naturally occurring antigen-specific T cells from convalescent donors that have already been selected and differentiated in the body. This inverts the logic from 'engineer specificity' to 'utilize pre-existing specificity'.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The T cells are stimulated in vitro using the patient's own viral antigens, allowing them to self-select and self-differentiate into the desired effector phenotype without requiring external genetic modification or complex conditioning protocols.

Inventive Principle:

Principle #25Self-service

4Duration of action of stationary object

If T cells from convalescent donors are used, then persistence and amplification are achieved, but graft versus host disease occurs

Engineering Contradiction:

ImprovepersistenceVSAvoidgraft versus host disease

Core Design Contradiction:

Duration of action of stationary objectVSObject-affected harmful factors

Solution Approach 1:

The invention selectively enriches for T cell subpopulations with specific phenotypic characteristics (TEMRA and SLEC) that have different functional properties and safety profiles compared to conventional T cell therapies, creating a localized quality improvement within the cellular product.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention uses a partial population of T cells (specific subpopulations) rather than all T cells from the donor, focusing only on the subset with desired characteristics while excluding potentially harmful cells, thereby reducing the risk of graft versus host disease.

Inventive Principle:

Principle #16Partial or excessive action

Data Source

PatentUS20240415887A1Terminal effector t cells, process for their production and their isolation and their therapeutic use

Publication Date: 2024.12.19 UNIVERSITE GRENOBLE ALPES

AI summary

An in vitro or ex vivo method for producing and isolating a cell subpopulation including T cells specific for an antigen linked to a disease of interest, which includes steps of obtaining, from an isolated human biological sample, a population of mononuclear cells including T cells specific for the antigen with a high proliferative capacity, culturing these mononuclear cells in a suitable cell culture medium containing the antigen, and isolating T cells specific to the antigen which do not express the CD45RO and CD27 markers at their surface. The cell subpopulation thus obtained and isolated finds application in particular for the treatment of the disease of interest.