CAR T Cell JAK-STAT Overexpression for Multi-Cytokine Persistence
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Solution Overview
Problem
Current treatments for cancer lack effective compositions and methods to enhance the efficacy and persistence of genetically engineered immune cells, such as CAR T cells, in treating diseases or disorders.
Innovation Solution
Administering modified immune cells, such as T cells, with overexpressed JAK2V617F, JAK3M511I, or chimeric G-CSFR/IL2Rβ/IL2Ry receptors, along with cytokines and JAK inhibitors like ruxolitinib, to enhance cell proliferation and persistence in vivo and ex vivo.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR T cell therapy is used, then cancer treatment is provided, but the efficacy and persistence of the immune cells are insufficient
Solution Approach 1:
The patent applies parameter changes by introducing specific mutations in JAK2 (V617F) and JAK3 (M511I) genes to modify the signaling parameters of CAR T cells. These genetic modifications alter the kinase activity and downstream signaling pathways, enabling enhanced proliferation, survival, and persistence of the immune cells in vivo, thereby resolving the contradiction between providing cancer treatment and achieving sufficient efficacy and persistence
Solution Approach 2:
The patent employs composite materials by combining CAR T cells with multiple modified signaling molecules (JAK2V617F, JAK3M511I, and/or chimeric G-CSFR/IL2Rβ/IL2Ry receptors) within the same cell system. This composite approach creates a synergistic effect where the combined signaling pathways amplify the therapeutic response and extend cell persistence, directly addressing the insufficiency of conventional single-pathway CAR T cell therapy
2Productivity
If JAK2V617F, JAK3M511I, or chimeric G-CSFR/IL2Rβ/IL2Ry are overexpressed in CAR T cells, then cell expansion and persistence are enhanced, but the complexity of cell modification increases
Solution Approach 1:
The patent applies segmentation by dividing the cell modification process into distinct modular components: (1) CAR expression plasmid, (2) JAK2V617F or JAK3M511I expression plasmid, and (3) chimeric G-CSFR/IL2Rβ/IL2Ry expression plasmid. Each plasmid can be independently designed, manufactured, and quality-controlled, then combined through transfection to achieve the desired multi-functional CAR T cell phenotype, thereby managing the complexity of cell modification
Solution Approach 2:
The patent uses an intermediary approach by employing viral vectors or non-viral delivery systems as mediators to introduce the modified signaling genes into CAR T cells. These delivery intermediaries simplify the overall process by providing a standardized mechanism for gene transfer, avoiding the need for complex direct genetic manipulation and enabling scalable production of modified cells
3Reliability
If cytokines and JAK inhibitors are administered with modified immune cells, then therapeutic efficacy is improved, but the treatment protocol complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-modifying the immune cells with the signaling mutations and cytokine receptors before administration to the patient. The cells are engineered ex vivo to contain the enhanced signaling capacity, so that upon in vivo activation by tumor antigens, they can immediately exhibit improved expansion and persistence without requiring complex concurrent pharmacological intervention, thereby simplifying the overall treatment protocol
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 modified immune cells exhibit increased expansion and persistence, offering improved therapeutic outcomes by enhancing the activity and potency of CAR T cells, potentially leading to better cancer treatment efficacy.
Implementation Method 1
The present invention provides compositions and methods for delivering multi-cytokine signals by overexpression of wild-type or mutant signal transduction molecules in lymphocytes (e.g. CAR T cells) both in vivo and ex vivo
Implementation Method 2
a chimeric receptor comprising Granulocyte Colony Stimulating Factor Receptor (G-CSFR), Interleukin-2 Receptor Beta (IL2RB), and Interleukin-2 Receptor Gamma (IL2RY)
Data Source
AI summary
The present disclosure provides methods for delivering multi-cytokine signals by overexpressing wild-type or mutant signal transduction molecules in lymphocytes (e.g. CAR T cells). Compositions and methods of treatment are also provided.