DARIC Immune Switch Dosing to Limit CAR T Toxicity and Exhaustion
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Solution Overview
Problem
Existing CAR T cell therapies face challenges with safety issues such as cytokine release syndrome and neurotoxicity, as well as efficacy challenges like antigen escape and T cell exhaustion, necessitating a controlled activation platform.
Innovation Solution
The development of a dimerizing agent regulated immunomodulatory complex (DARIC) that utilizes rapamycin or analogs to induce multimerization of fusion proteins, allowing controlled activation and reducing immunosuppressive effects and immune cell exhaustion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cell therapies are activated to kill cancer cells, then efficacy against tumors is improved, but safety issues such as cytokine release syndrome and neurotoxicity occur
Solution Approach 1:
The patent applies preliminary action by designing CAR T cells with dormant signaling capabilities that are activated only after targeted antigen recognition. The switch mechanism is pre-installed but remains inactive until the T cell encounters its target antigen, ensuring that therapeutic activation occurs only when needed and only in the presence of cancer cells, thereby preventing premature cytokine release syndrome and neurotoxicity
Solution Approach 2:
The patent introduces an intermediary switch mechanism that mediates between antigen recognition and full T cell activation. This switch acts as a controlled intermediary step that allows gradual or regulated activation signaling, preventing direct and uncontrolled cytokine release while still enabling effective anti-tumor responses through controlled immune activation
2Ease of operation
If dimerizing agents are used to activate immunomodulatory complexes, then controlled T cell activation is achieved, but immunosuppressive effects and immune cell exhaustion may occur
Solution Approach 1:
The patent applies partial action by using dimerizing agents at controlled concentrations and dosing schedules that provide sufficient activation signal to overcome exhaustion without excessive stimulation that would cause immunosuppression. The switch mechanism allows partial activation states that maintain T cell functionality while avoiding the harmful effects of over-activation
Solution Approach 2:
The patent employs periodic action through controlled dosing schedules of dimerizing agents that provide activation signals in periodic intervals. This periodic stimulation maintains T cell activation and prevents exhaustion by allowing rest periods between activation cycles, thereby sustaining long-term anti-tumor immunity without causing immunosuppressive effects
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 DARIC platform provides controlled immune cell activation, improving toxicity profiles and preventing exhaustion, thereby enhancing the efficacy of CAR T cell therapies.
Implementation Method 1
inducing the multimerization of at least a first fusion protein and a second fusion protein to thereby form the dimerizing agent regulated immunomodulatory complex
Implementation Method 2
modulating the multimerization of a first fusion protein including a first multimerization domain (e.g., FKBP-rapamycin binding (FRB) or FK506 binding protein (FKBP)) and a second fusion protein including a second multimerization domain (e.g., FKBP-rapamycin binding (FRB) or FK506 binding protein (FKBP)) using rapamycin or analogs thereof for the formation of the DARIC
Data Source
AI summary
Methods and compositions for priming a dimerizing agent regulated immunomodulatory complex for signaling by inducing the multimerization of at least a first fusion protein and a second fusion protein to thereby form the dimerizing agent regulated immunomodulatory complex are described. The methods and compositions utilize dimerizing agent dosing schedules designed to: (i) maintain specified blood trough levels of the dimerizing agent, (ii) allow activation of the immunomodulatory complex; (iii) reduce or avoid potential immunosuppressive effects of the dimerizing agent, (iv) reduce or avoid immune cell exhaustion, and/or (v) reduce or avoid side effects associated with activation of the immunomodulatory complex.