NKG2D CAR Cells Secreting IL-18 to Counteract Tumor Immunosuppression
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Solution Overview
Problem
Current CAR-T cell therapies face challenges in effectively targeting solid tumors due to the immunosuppressive tumor microenvironment, and existing solutions often come with significant toxicity.
Innovation Solution
Engineering cells to express a chimeric NKG2D receptor (CAR) in combination with IL-18, which is secreted to reduce immunosuppression and enhance anti-tumor activity, thereby improving treatment efficacy and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to target solid tumors, then anti-tumor activity is improved, but the immunosuppressive tumor microenvironment reduces treatment efficacy
Solution Approach 1:
The patent introduces IL-18 as an intermediary substance that mediates between the CAR-T cell and the tumor microenvironment. The IL-18 protein is secreted by the engineered cells to counteract immunosuppression, acting as a chemical mediator that reverses the harmful effects of the tumor microenvironment and enhances anti-tumor immunity
Solution Approach 2:
The patent changes the functional parameters of the CAR-T cell by engineering it to secrete IL-18. This parameter change transforms the cell from a simple antigen-targeting vehicle into an active immunomodulator that can dynamically alter the tumor microenvironment's immunosuppressive state, thereby improving reliability against solid tumors
2Reliability
If cytokines are secreted to protect CAR-T cells from suppressive tumor microenvironment, then treatment efficacy is improved, but significant toxicity occurs
Solution Approach 1:
The patent converts the harmful effect of the immunosuppressive tumor microenvironment into a beneficial outcome by using IL-18 to reverse immunosuppression. The IL-18 secretion transforms the adverse microenvironment conditions into a pro-inflammatory, anti-tumor state, achieving treatment efficacy without the severe toxicity associated with other cytokine approaches
3Adaptability or versatility
If NKG2D CAR is used to target stress-induced ligands, then both liquid and solid tumors can be treated, but immunosuppression in the tumor microenvironment limits effectiveness
Solution Approach 1:
The patent merges two functions into a single engineered cell: (1) the NKG2D CAR's ability to recognize stress-induced ligands on various tumor types, and (2) the IL-18 secretion capability to counteract immunosuppression. This combination allows the cell to maintain versatility in targeting different tumors while simultaneously improving effectiveness by reversing microenvironmental suppression
Data Source
AI summary
The present application relates to the field of immunotherapy, more particularly to the field of adoptive cell therapy (ACT). Here, NKG2D CAR expressing cells that also express IL-18 are proposed. Also proposed are polynucleotides, vectors encoding the NKG2D CAR and IL-18 and cells expressing both. These cells are particularly suitable for use in immunotherapy, including allogeneic therapy. The invention provides methods of increasing the efficacy of a T cell therapy in a patient in need thereof. Further, strategies to treat diseases such as cancer using these cells are also provided. The engineered immune cells, such as T-cells or natural killer (NK) cells, expressing such CARs are suitable for treating lymphomas, multiple myeloma and leukemia, but other tumors can be treated as well, depending on the specificity of the CAR. Most notably, as expression and secretion of the pro-inflammatory cytokine IL-18 is beneficial to reducing the immunosuppressive effect of the tumor microenvironment, treatment of solid tumors is envisaged.