Constitutively Active Chimeric Cytokine Receptors for CAR-T Cell Potency
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Solution Overview
Problem
Current approaches to providing cytokine support for CAR-T cell therapy are limited by systemic toxicity and bystander immune activation, which compromise therapeutic efficacy.
Innovation Solution
Development of constitutively active chimeric cytokine receptors (CACCRs) that allow for increased immune cell activation, proliferation, persistence, and potency by targeting cytokine signals specifically to CAR-T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If systemic infusions of recombinant cytokines or extracellular cytokine secretion by CAR-T cells is used to provide cytokine support, then immune cell activation and proliferation is enhanced, but systemic toxicity and bystander host immune activation occur
Solution Approach 1:
The invention applies local quality by making the cytokine signaling capability specific to CAR-T cells through the chimeric cytokine receptor design. The CACCR is expressed only on CAR-T cells, providing cytokine support locally where needed rather than systemically. This selective expression pattern enhances immune cell activation and proliferation in the therapeutic context while avoiding bystander effects on other immune cells and systemic toxicity.
Solution Approach 2:
The invention segments the cytokine signaling function by creating a separate chimeric cytokine receptor component that can be independently expressed on CAR-T cells. This segmentation allows the cytokine support function to be decoupled from systemic cytokine administration, enabling targeted delivery of immune-potentiating signals specifically to the engineered immune cells that express the CACCR.
2Productivity
If constitutively activated dimerized cytokine receptor (IL-7Ra) is introduced to provide cytokine support, then immune cell signaling is enhanced, but the nature and magnitude of signaling output is limited
Solution Approach 1:
The chimeric cytokine receptor design incorporates a universal cytokine signaling domain (IL-2 receptor gamma chain) that can provide constitutive signaling while maintaining adaptability. The CACCR structure combines this universal signaling component with CAR-specific targeting, allowing the receptor to provide flexible magnitude and nature of signaling output that can be tuned through different design parameters while maintaining constitutive activation capability.
3Productivity
If Signal 3 is incorporated directly into the CAR molecule, then cytokine support is provided, but the strength of Signal 3 depends on CAR activation strength
Solution Approach 1:
The chimeric cytokine receptor provides preliminary action by establishing constitutive cytokine signaling capability before CAR activation is required. The CACCR is designed to be constitutively active, providing Signal 3 support independently of target engagement or CAR activation status. This ensures that immune-potentiating cytokine signals are available to enhance CAR-T cell function, persistence, and proliferation regardless of the activation state of the CAR component.
Data Source
AI summary
Provided herein are constitutively active chimeric cytokine receptors (CACCRs). When present on chimeric antigen receptor (CAR)-bearing immune cells, such CACCRs allow for increased immune cell activation, proliferation, persistence, and/or potency. Also provided are methods of making and using the CACCRs described herein.