Dasatinib Modulation of CAR-T Cell Kinase Activity

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Solution Overview

Problem

Current CAR-T cell therapy for cancer is limited by severe side effects such as cytokine release syndrome and the inability to control the function of CAR-T cells after infusion, leading to inefficacy and safety concerns.

Innovation Solution

The use of dasatinib, a tyrosine kinase inhibitor, to block or augment CAR-T cell function through continuous or intermittent administration, allowing for precise control of CAR-T cell activity and mitigating side effects while maintaining antitumor efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR-T cell therapy is administered to treat cancer, then antitumor efficacy is improved, but severe side effects such as cytokine release syndrome occur

Engineering Contradiction:

Improveantitumor efficacyVSAvoidcytokine release syndrome

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces dasatinib as an intermediary substance that mediates between the CAR-T cell therapy and the patient's system. Dasatinib selectively modulates CAR-T cell activity by inhibiting specific kinases, thereby reducing harmful cytokine release while preserving antitumor efficacy. This intermediary approach allows control over the immunotherapeutic response without directly modifying the CAR-T cells themselves.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the functional parameters of CAR-T cells through pharmacological modulation by dasatinib. By altering kinase activity levels, the treatment shifts CAR-T cell behavior from a hyperactivated state (causing cytokine release syndrome) to a controlled state that maintains cytotoxic function against tumors while reducing harmful inflammatory responses.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If CAR-T cell function is enhanced to improve antitumor potency, then therapeutic efficacy is improved, but control over CAR-T cell activity is lost

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidcontrol over CAR-T cell activity

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent implements a feedback control mechanism where dasatinib administration is adjusted based on monitored CAR-T cell activity and patient response. Blood tests measuring cytokine levels and CAR-T cell expansion guide dosing decisions, creating a closed-loop system that maintains therapeutic efficacy while preventing excessive activation and enabling real-time control over treatment intensity.

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS20230310432A1Control and modulation of the function of gene-modified chimeric antigen receptor t cells with dasatinib and other tyrosine kinase inhibitors

Publication Date: 2023.10.05 JULIUS MAXIMILIANS UNIV WURZBURG

AI summary

The invention relates to the immunomodulatory features of dasatinib and other tyrosine kinase inhibitors towards genetically modified immune cells. The invention encompasses the indication of dasatinib and other tyrosine kinase inhibitors as an immune cell inhibitor as well as an enhancer of immune cells depending on the dosing and schedule of treatment, the administration routes, the susceptible receptor variants and the treatable cell types which can be used for immunotherapy.