T-Cell Engager CRS Mitigation Using JAK or mTOR Inhibitors
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Solution Overview
Problem
Current treatments for T cell engaging agents like T cell bispecific antibodies (TCBs) or chimeric antigen receptor (CAR) expressing T cells (CAR-T cells) suffer from cytokine release syndrome (CRS) due to on-target on-tumor, on-target off-tumor cytotoxic activity, with existing inhibitors like dasatinib causing unintended functional suppression of T cells.
Innovation Solution
The use of inhibitors of JAK and/or mTOR signaling, such as temsirolimus, sirolimus, everolimus, and ruxolitinib, to mitigate CRS while preserving TCB-mediated target cell killing by uncoupling cytokine release from therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell engaging agents are administered to treat cancer, then therapeutic efficacy is improved, but cytokine release syndrome occurs causing harmful side effects
Solution Approach 1:
The patent introduces a blocking antibody as an intermediary agent that specifically binds to and neutralizes cytokines (such as IL-6, IFN-γ, TNF-α) released during T cell engaging therapy. This mediator intercepts the harmful cytokines before they can cause severe CRS, while allowing the T cell engaging agent to continue its therapeutic action against tumor cells.
Solution Approach 2:
The patent extracts and removes the harmful component (cytokines) from the system by administering blocking antibodies that specifically bind to these cytokines. This separates the therapeutic effect (T cell-mediated tumor killing) from the harmful effect (cytokine-mediated CRS), allowing the beneficial activity to continue while neutralizing the adverse reactions.
2Object-affected harmful factors
If blocking antibodies against individual cytokines are used to prevent CRS, then harmful side effects are reduced, but TCB-induced T cell activity may be affected
Solution Approach 1:
The patent applies blocking antibodies with specific local quality - each antibody is designed to target a specific cytokine (IL-6, IFN-γ, or TNF-α) rather than broadly suppressing all immune activity. This localized approach allows selective neutralization of harmful cytokines while preserving other essential T cell functions and therapeutic activity.
Solution Approach 2:
The patent uses partial action by administering blocking antibodies at doses and timing that provide sufficient neutralization of harmful cytokines without completely suppressing the immune response. The blocking is partial and selective, allowing enough cytokine activity to maintain T cell functionality while preventing severe CRS.
Data Source
AI summary
The present invention relates to the prevention or mitigation of adverse effects related to T cell engaging agents, such as cytokine release syndrome. Specifically, the invention relates to the prevention or mitigation of such side effects using an inhibitor of JAK and/or mTOR.