Chimeric Lactate Receptor T Cells Overcoming Metabolic Inhibition
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Solution Overview
Problem
T cell therapies for cancer, particularly in solid tumors like high-grade glioma, are hindered by immunosuppression caused by the tumor's metabolic landscape, which restricts glucose access and impairs T cell function.
Innovation Solution
Engineering T cells with chimeric lactate receptors that combine a lactate receptor domain with intracellular signaling domains, such as CD28, to enhance T cell glycolysis, activation, and tumor targeting in the presence of lactate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are used to treat cancer, then cancer treatment efficacy is improved, but T cell function is impaired due to glucose restriction and lactate inhibition in the tumor microenvironment
Solution Approach 1:
The patent converts the harmful inhibitory effect of lactate on T cells into a beneficial activation signal. By engineering T cells to express chimeric receptors that bind lactate and trigger activating signals, the tumor microenvironment's lactate abundance transforms from a suppressive factor into a pro-activation factor, enhancing T cell response where it is most needed.
Solution Approach 2:
The patent modifies the signaling parameter of lactate perception by introducing chimeric receptors with specific intracellular signaling domains (e.g., CD28, CD3-zeta). This changes the biological response parameter from inhibition to activation, allowing T cells to respond positively to lactate concentrations that would normally suppress their function.
2Reliability
If T cells are engineered with chimeric lactate receptors, then resistance to lactate inhibition is improved, but device complexity increases
Solution Approach 1:
The chimeric receptor is segmented into distinct functional modules: an extracellular lactate-binding domain (using the structure of the LacR receptor) and an intracellular signaling domain (using established T cell signaling components like CD28 or CD3-zeta). This modular design allows independent optimization of ligand binding and signaling functions while using well-characterized building blocks to manage complexity.
Solution Approach 2:
The patent employs universal signaling domains (CD28, CD3-zeta, 4-1BB) that can be integrated into various receptor contexts and provide consistent activating signals. These multi-functional signaling modules can be combined with different extracellular domains to create receptors with specialized ligand binding while maintaining a common activation mechanism, reducing the need for entirely new signaling components.
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 engineered T cells are resistant to lactate-induced inhibition and can effectively activate and proliferate, even in lactate-rich tumor microenvironments, thereby overcoming metabolic barriers to enhance cancer treatment efficacy.
Implementation Method 1
The lactate receptor domain can be, but is not limited to, LacR or a lactate binding fragment thereof. Binding of a lactate to the lactate receptor domain results in the intracellular signaling domain delivering a signal to, or activating, the T cell.
Implementation Method 2
The engineered T cells use lactate signaling to enhance T cell glycolysis, activation, and tumor targeting. The intracellular signaling domain generates a signal that promotes proliferation, activation, differentiation, or an immune function in a cell expressing the chimeric lactate receptor.
Data Source
AI summary
Described are chimeric lactate receptors that act a molecular switches. A chimeric lactate receptor comprises a lactate receptor linked to one or more intracellular signaling domains. Also described are nucleic acids encoding the chimeric lactate receptors, T cell expressing the chimeric lactate receptors, and method of using the T cells to treat cancer.