IL-10 Expressing CAR T Cells for Solid Tumor Exhaustion
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Solution Overview
Problem
Current CAR T cell therapies for solid tumors face challenges due to T cell exhaustion, characterized by suppressed mitochondrial respiration and metabolic fitness, leading to suboptimal antitumor effects, as existing metabolic interventions are not sufficient to fully rescue T cells from exhaustion.
Innovation Solution
Engineering immune cells, such as T cells, to express interleukin-10 (IL-10) or its variants, combined with chimeric antigen receptors (CARs) or T cell receptors (TCRs), to enhance metabolic fitness, proliferation, and antitumor activity by promoting oxidative phosphorylation and memory-like states.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used to treat solid tumors, then antitumor activity is improved, but T cell exhaustion occurs leading to suppressed mitochondrial respiration and metabolic fitness
Solution Approach 1:
The patent introduces an intermediary substance (metabolic supplement such as IL-15, IL-21, or other metabolites) that mediates between the T cell and the tumor microenvironment. This intermediary rescues exhausted T cells by enhancing mitochondrial respiration and metabolic fitness without directly targeting the tumor, thereby resolving the contradiction between maintaining antitumor activity and preserving mitochondrial function
Solution Approach 2:
The patent changes the metabolic parameters of T cells by administering metabolic supplements that shift T cell metabolism from glycolysis to oxidative phosphorylation. This parameter change restores mitochondrial respiration and metabolic fitness, allowing T cells to maintain antitumor activity without exhaustion in the solid tumor microenvironment
2Stability of the object's composition
If metabolic intervention is applied during expansion phase, then T cell differentiation is modulated, but antitumor effect remains suboptimal
Solution Approach 1:
The patent applies metabolic intervention during the expansion phase as a preliminary action to prime T cells for enhanced antitumor activity. By modulating T cell differentiation and metabolic fitness in advance, the T cells are better prepared to withstand the tumor microenvironment and exert sustained antitumor effects, resolving the suboptimal outcome
Solution Approach 2:
The patent ensures continuous metabolic support by administering metabolic supplements throughout the expansion phase and into the effector phase. This continuity maintains T cell metabolic fitness and differentiation status, ensuring sustained antitumor activity rather than transient effects that would diminish over time
Data Source
AI summary
The present invention relates generally to the field of anti-cancer therapy, in particular to the use of adoptive T cell transfer therapy for treating cancer, in particular sold tumors. More specifically, the present invention relates to immune cells comprising one or more recombinant constructs, wherein at least one recombinant construct encodes an interleukin-10, a fragment or a variant thereof.