Engineered Immune Cells for Nutrient-Poor Tumor Microenvironments
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The tumor microenvironment is often nutrient-limited, particularly in terms of oxidized nicotinamide adenine dinucleotide (NAD) and oxidized carbon, which hampers immune cell activation and cancer immunotherapy efficacy, as seen in solid tumors with high lactate levels and poor perfusion.
Innovation Solution
Administering immune cells engineered to express exogenous enzymes like NADH oxidase that oxidize NADH to NAD+, or agents that inhibit glucose metabolism in tumor cells, along with providing one-carbon units to enhance metabolic fuel availability and promote anti-tumor immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune cells are administered to treat cancer, then anti-tumor immune response is enhanced, but the tumor microenvironment's nutrient limitations (low oxidized NAD, low oxidized carbon, high lactate) suppress immune cell activation and reduce therapy efficacy
Solution Approach 1:
The patent introduces formate as an intermediary substance that tumor cells cannot utilize but immune cells can metabolize. Formate serves as a carbon source and one-carbon unit donor that indirectly supports oxidized NAD production in immune cells without being consumed by tumor cells, thus mediating the metabolic conflict between immune cells and tumor cells in the nutrient-limited microenvironment
Solution Approach 2:
The patent changes the metabolic parameters of the tumor microenvironment by administering formate, which alters the availability of one-carbon units and metabolic fuels. This parameter change shifts the metabolic balance to favor immune cell activation and function while depriving tumor cells of usable carbon sources, thereby resolving the nutrient limitation problem
2Reliability
If glucose is provided to support immune cell activation, then immune response is enhanced, but tumor cells consume glucose preferentially, creating a barrier to immune cell activation
Solution Approach 1:
The patent converts the harmful effect of glucose consumption by tumor cells into a beneficial outcome by providing formate instead. Since tumor cells lack the metabolic pathways to utilize formate, this alternative carbon source bypasses the glucose consumption problem and directly benefits immune cells that can metabolize formate through the formate dehydrogenase pathway, thereby converting the metabolic conflict into a therapeutic advantage
3Reliability
If the tumor microenvironment is nutrient-limited to starve tumor cells, then tumor growth is inhibited, but immune cells also suffer from nutrient deprivation and cannot activate effectively
Solution Approach 1:
The patent applies local quality by providing formate specifically to the tumor microenvironment where it creates a selective metabolic advantage for immune cells. Formate metabolism is localized to immune cells through the expression of formate dehydrogenase, creating a spatially and functionally differentiated metabolic landscape where immune cells can thrive on formate while tumor cells remain starved of usable carbon sources
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 approach creates a more favorable metabolic environment for immune cell activation, enhancing anti-tumor immune responses and improving the efficacy of immunotherapy, including CAR-T therapy, by increasing oxidized NAD and carbon levels and reducing lactate levels in the tumor microenvironment.
Implementation Method 1
administering to a subject a population of immune cells that express an exogenous enzyme (e.g., NADH oxidase) that catalyzes the oxidation of nicotinamide adenine dinucleotide, reduced form (NADH) to nicotinamide adenine dinucleotide, oxidized form (NAD+)
Implementation Method 2
exogenous enzyme (e.g., NADH oxidase) that catalyzes the oxidation of nicotinamide adenine dinucleotide, reduced form (NADH) to nicotinamide adenine dinucleotide, oxidized form (NAD+)
Data Source
AI summary
The present invention provides, in some embodiments, methods of promoting an immune response in a subject in need thereof, comprising administering to a subject a population of immune cells that express an exogenous enzyme that facilitates immune cell function in a nutrient-poor environment. Other embodiments of the invention include methods of promoting an immune response to a tumor in a subject in need thereof, comprising administering to the subject an effective amount of an agent that provides a one-carbon unit (e.g., formate) and an agent that promotes an anti-tumor response, and methods of promoting an immune response to a tumor in a subject in need thereof, comprising administering to a subject an effective amount of an agent that inhibits consumption of metabolic fuels by tumor cells. The invention also provides, in other embodiments, compositions comprising an ex vivo population of immune cells expressing an exogenous enzyme that enhances immune cell function in nutrient poor environments, and compositions comprising a nucleic acid expression construct encoding an inhibitor of glucose metabolism, and a pharmaceutically acceptable carrier or excipient.