ACKR2 Modulators for Tumor Immune Cell Infiltration
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cancer immunotherapies, particularly immune checkpoint blockades, have limited efficacy for non-responsive patients due to the lack of infiltration of cytotoxic immune cells into tumor microenvironments, which are often 'cold' and not inflamed.
Innovation Solution
Development of specific ACKR2 modulators that block the scavenging of CXCL10 and CCL5, increasing the infiltration of NK and CD8+ T cells into tumor microenvironments by enhancing the bioavailability of these chemokines, thereby converting 'cold' tumors to 'hot' inflamed microenvironments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint blockade therapy is used, then cancer treatment is provided, but efficacy is limited for non-responsive patients due to lack of immune cell infiltration
Solution Approach 1:
The patent introduces ACKR2 modulators as intermediary substances that mediate between the existing immunotherapy approach and the desired outcome of increased immune cell infiltration. These modulators specifically target ACKR2 receptors to enhance chemokine signaling, thereby facilitating T cell and NK cell migration into the tumor microenvironment without requiring a complete change from the existing ICB therapy framework.
Solution Approach 2:
The patent changes the biochemical parameters of the tumor microenvironment by modulating ACKR2 receptor activity. This alters the chemokine gradient parameters and signaling efficiency, creating conditions that promote immune cell infiltration. The modulators adjust receptor-ligand binding parameters to optimize chemokine-mediated cell recruitment while maintaining compatibility with existing immunotherapies.
2Object-affected harmful factors
If ACKR2 modulators are used to increase chemokine bioavailability, then immune cell infiltration is enhanced, but the complexity of the treatment regimen increases
Solution Approach 1:
The ACKR2 modulators developed in this patent possess multi-functionality by simultaneously addressing multiple aspects of the immunotherapy challenge: they enhance chemokine bioavailability, promote immune cell infiltration, and can be combined with various existing immunotherapies (anti-PD-1, anti-PD-L1, anti-CTLA-4). This universal applicability reduces the need for separate specialized treatments for different scenarios.
Solution Approach 2:
The modulators enable the tumor microenvironment to self-organize for immune cell recruitment by restoring natural chemokine gradients. Rather than requiring complex external control mechanisms, the system uses the modulators to re-establish endogenous signaling pathways that naturally guide immune cell infiltration, reducing the need for complex treatment monitoring and adjustment.
3Quantity of substance
If ACKR2 scavenging activity is blocked, then chemokine bioavailability increases, but specificity of the modulator must be maintained to avoid off-target effects
Solution Approach 1:
The patent applies local quality by designing modulators that specifically target ACKR2 receptors in the tumor microenvironment rather than uniformly affecting all chemokine receptors throughout the body. This localized action ensures that chemokine bioavailability is enhanced primarily where needed (in the tumor bed) while minimizing off-target effects on other physiological systems that depend on chemokine signaling.
Solution Approach 2:
The modulators are designed to preliminarily block ACKR2 scavenging activity before administering the full immunotherapy regimen. This preliminary action establishes the necessary chemokine gradient conditions in advance, ensuring that subsequent immunotherapies can effectively recruit immune cells without requiring high doses or complex combination protocols that might cause off-target 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 use of ACKR2 modulators improves the response of cancer patients to immunotherapy by increasing immune cell infiltration into tumors, enhancing the therapeutic benefit of immune checkpoint inhibitors.
Implementation Method 1
ACKR2 binds and scavenges the C-X-C motif chemokine 10 (CXCL10) and that a specific ACKR2 (i.e. an ACKR2-specific) modulator that blocks the scavenging of CCL5 and/or CXCL10
Implementation Method 2
a specific ACKR2 modulator that blocks the scavenging of CCL5 and/or CXCL10 can increase the infiltration of NK and CD8+ T cells into the tumor microenvironment
Data Source
AI summary
The application discloses a specific ACKR2 modulator for use in the treatment of a proliferative disease or disorder in a subject and/or for use in improving the response of a subject to anticancer immunotherapy. The application further discloses pharmaceutical compositions comprising such a specific ACKR2 modulator and one or more immune checkpoint modulators, preferably one or more immune checkpoint inhibitors.