T Cell Expansion Using P38 MAPK Inhibitors

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Solution Overview

Problem

Adoptive cell therapy using cancer-reactive T cells faces challenges in expanding T cells without inducing a terminally differentiated phenotype, which diminishes antitumor activity and reduces long-term persistence in vivo.

Innovation Solution

Culturing isolated T cells with antigenic specificity for cancer antigens in the presence of a p38 mitogen-activated protein kinase (MAPK) inhibitor to maintain their capacity for targeting cancer cells and promote transcriptional, metabolic, and functional properties associated with long-lived memory T cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If T cells are expanded in number through conventional culturing methods, then the quantity of T cells increases, but the T cells develop a terminally differentiated phenotype that reduces their antitumor activity and long-term persistence

Engineering Contradiction:

Improvenumber of T cellsVSAvoidantitumor activity and long-term persistence

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies parameter changes by modifying the chemical environment during T cell culture through the addition of p38 MAPK inhibitors (such as SB203580, SB202190, or BIRB 796). This chemical parameter change prevents the terminal differentiation of T cells while allowing their expansion, thereby maintaining both the quantity increase and the functional reliability of the T cells for antitumor therapy

Inventive Principle:

Principle #35Parameter changes

2Productivity

If T cells are cultured to achieve high expansion numbers, then productivity increases, but the functional quality and therapeutic efficacy of the T cells deteriorate

Engineering Contradiction:

ImproveT cell expansion efficiencyVSAvoidtherapeutic efficacy

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent resolves this contradiction by changing the chemical parameter of the culture system through p38 MAPK inhibition. This enables high-productivity T cell expansion while preserving therapeutic efficacy, as the inhibitor prevents the loss of functional quality that normally occurs during extensive culture expansion

Inventive Principle:

Principle #35Parameter changes

3Ease of manufacture

If conventional T cell expansion methods are used, then the ease of manufacture is improved, but the functional properties of the T cells for long-term persistence are compromised

Engineering Contradiction:

Improvesimplicity of T cell expansion processVSAvoidlong-term persistence of T cells in vivo

Core Design Contradiction:

Ease of manufactureVSDuration of action of moving object

Solution Approach 1:

The patent maintains ease of manufacture by using a simple chemical addition (p38 MAPK inhibitor) to the existing culture process, while dramatically improving the duration of action through enhanced long-term persistence. The inhibitor is added during standard culture expansion, requiring minimal process modification but yielding T cells with superior in vivo persistence characteristics

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20200316122A1Methods of producing t cell populations using p38 MAPK inhibitors

Publication Date: 2020.10.08 THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY DEPARTMENT OF HEALTH & HUMAN SERVICES

AI summary

Provided are methods of producing an isolated population of T cells for adoptive cell therapy, the method comprising culturing isolated T cells in vitro in the presence of a p38 mitogen activated protein kinase (p38 MAPK) inhibitor, wherein the T cells have antigenic specificity for a cancer antigen. Also provided are related isolated populations of T cells, pharmaceutical compositions, and methods of treating or preventing cancer in a mammal.