MPC Inhibition for T-Cell Memory Phenotype Generation
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Solution Overview
Problem
Current strategies for expanding T-cells for adoptive cell transfer immunotherapy often result in terminally differentiated cells, leading to inefficient engraftment and cancer recurrence, as they fail to induce a self-renewing memory phenotype, which is crucial for sustained anti-tumor responses.
Innovation Solution
Inhibiting the mitochondrial pyruvate carrier (MPC) during CD8 T-cell priming in vitro leads to metabolic adaptations that increase mitochondrial oxygen consumption, enhance central memory marker expression, and promote epigenetic modifications, resulting in a higher proportion of central memory cells with improved anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If T-cells are expanded in vitro for adoptive cell transfer, then the quantity of T-cells increases, but the cells become terminally differentiated with reduced persistence and engraftment efficiency
Solution Approach 1:
The patent applies parameter changes by modifying the metabolic state of T-cells through MPC inhibition during in vitro expansion. This metabolic parameter change prevents terminal differentiation while maintaining cell proliferation, thereby producing large quantities of T-cells that retain memory phenotype characteristics and exhibit improved persistence and engraftment efficiency in vivo
Solution Approach 2:
The patent employs preliminary action by pre-treating T-cells with MPC inhibitors during the expansion phase before adoptive transfer. This preliminary metabolic intervention programs the cells to adopt a memory-like phenotype in advance, ensuring they are primed for long-term persistence and effective engraftment upon transplantation into the patient
2Strength
If T-cells are differentiated into effector cells with high cytotoxic potential, then anti-tumor activity increases, but the cells become short-lived and terminally differentiated
Solution Approach 1:
The patent utilizes parameter changes by blocking the MPC pathway to alter metabolic flux from glycolysis toward oxidative phosphorylation. This metabolic reprogramming enables T-cells to maintain high cytotoxic potential while acquiring the metabolic characteristics of memory cells, thereby extending their lifespan without sacrificing anti-tumor functionality
Solution Approach 2:
The patent converts the typically harmful effect of metabolic inhibition (which can suppress cell function) into a beneficial outcome. By selectively inhibiting MPC, the patent redirects metabolism to support both sustained cell survival and maintained cytotoxic activity, transforming a potentially detrimental intervention into a therapeutic advantage
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 approach effectively generates and maintains T-cells with a memory phenotype, enhancing their therapeutic potential by increasing persistence and anti-tumor activity upon adoptive transfer, as demonstrated by improved tumor control and cytokine production in mouse models.
Implementation Method 1
contacting activated T-cells with an inhibitor of the mitochondrial pyruvate carrier (MPC inhibitor)
Data Source
AI summary
The present invention relates to an in vitro cell culture method comprising a step of contacting T-cells with an MPC inhibitor, and further to a cell population comprising T-cells with a memory phenotype obtained by said method, preferably, wherein the T-cells are human cells. The present invention also relates to a method for generating and/or maintaining T-cells and/or B-cells with a memory phenotype comprising the steps of culturing T-cells and or B-cells in vitro and adding an MPC inhibitor to the culture. The invention furthermore relates to a population of T-cells and/or B-cells obtained by the methods of the invention. Also provided are immunotherapies using the cells of the invention. Furthermore, provided is an MPC inhibitor for use in immunotherapy and/or as a vaccine co-adjuvant.