PHGDH-Engineered Immune Cells for Persistent Cancer and Infection Therapy
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Solution Overview
Problem
Current cellular therapies, particularly CAR T cell therapies, face challenges with insufficient cell persistence and survival, limiting their effectiveness in treating cancers and infections.
Innovation Solution
Genetically engineering cells to enforce expression of phosphoglycerate dehydrogenase (PHGDH), which functions as an RNA binding protein to regulate cell differentiation and survival, enhancing persistence and reducing apoptosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cellular therapy is used to treat cancer and infections, then therapeutic effectiveness is improved, but cell persistence and survival are insufficient
Solution Approach 1:
The patent changes the metabolic state of T cells by modulating the serine biosynthesis pathway. Specifically, it adjusts key metabolic parameters (enzyme activity, substrate availability) to shift T cells from glycolysis-dependent to oxidative phosphorylation-dependent metabolism, thereby improving cell persistence and survival without compromising therapeutic effectiveness
Solution Approach 2:
The patent enables continuous energy production in T cells by enhancing oxidative phosphorylation capacity. This continuous mitochondrial energy generation sustains T cell survival and function over extended periods, addressing the limitation of transient cell persistence in conventional cellular therapies
2Reliability
If immune cells are used to eliminate cancer cells, then anti-tumor response is improved, but cell survival and maintenance of activity are insufficient
Solution Approach 1:
The patent modifies metabolic parameters in effector T cells by upregulating serine biosynthesis pathway enzymes (PHGDH, PSAT1, PSR). This parameter change shifts the energy metabolism profile from glycolysis to oxidative phosphorylation, extending T cell survival duration while maintaining anti-tumor cytotoxicity and cytokine production
Solution Approach 2:
The patent applies preliminary metabolic conditioning to T cells before adoptive transfer. By pre-modulating the serine biosynthesis pathway and mitochondrial function ex vivo, the T cells are prepared with enhanced survival capabilities that persist during in vivo anti-tumor responses, thereby extending their functional duration
3Adaptability or versatility
If CAR T cell therapy is administered, then treatment potential is improved, but cell persistence over time is limited
Solution Approach 1:
The patent changes metabolic parameters in CAR T cells by enhancing serine biosynthesis capacity. This metabolic reprogramming increases mitochondrial biogenesis and oxidative phosphorylation efficiency, enabling CAR T cells to maintain their therapeutic potential against solid tumors and infections while extending their persistence duration from weeks to months
Solution Approach 2:
The patent introduces metabolic flexibility to CAR T cells by enabling dynamic switching between glycolysis and oxidative phosphorylation based on environmental conditions. This dynamic metabolic adaptation allows CAR T cells to survive in diverse tumor microenvironments and maintain long-term persistence without losing their antigen-specific cytotoxic function
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
Improved cellular therapies with increased cell persistence and survival, leading to more effective treatments for cancer and infections.
Implementation Method 1
PHGDH, which functions as an RNA binding protein to regulate cell differentiation and survival
Data Source
AI summary
The invention is in the field of regenerative medicine and provides compositions and methods for treating cancer and/or infections in patients. The invention provides cells, preferably immune cells, genetically engineered to enforce expression of PHGDH, and expression constructs, vectors and methods for preparing and using the same.