Decoupling Immunotherapy Toxicity from Efficacy: GPR183 Biomarker and Therapeutic Platform
This technology provides methods and compositions that use GPR183 expression in B cells and regulatory T cells (Tregs) to predict, prevent, and treat immune-related adverse events (irAEs) associated with cancer immunotherapy, while also enhancing anti-tumor immunity. By measuring and modulating GPR183-driven immune cell positioning in distinct immune compartments, this approach offers a path to uncouple the toxicity of checkpoint blockade therapy from its therapeutic benefit.
Description
Immune checkpoint blockade therapies can produce durable anti-tumor responses, but their clinical use is frequently limited by irAEs, and current management relies on broad immunosuppression that can compromise anti-tumor immunity. This technology is based on the discovery that GPR183, a G protein-coupled receptor that responds to oxysterol ligands, marks and regulates a disease-relevant immune cell positioning program in two distinct compartments: B cells associated with irAEs, and Tregs associated with tumor immune suppression. The core methods involve determining GPR183 expression levels in a biological sample to identify patients at increased risk of developing irAEs (when GPR183 is elevated in B cells) or patients whose tumors are enriched for an immunosuppressive Treg program (when GPR183 is elevated in tumor-associated Tregs). These biomarker readouts can then inform treatment decisions, including selecting patients for combination therapy with a GPR183 modulator alongside an anti-cancer treatment such as an immune checkpoint inhibitor.Applications
- Companion diagnostic assays to predict irAE risk prior to or during immune checkpoint blockade therapy- Biomarker-based patient stratification tools to identify tumors enriched for immunosuppressive Treg programs
- Combination therapeutics pairing GPR183 modulators with immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4) to improve efficacy while reducing toxicity
- Diagnostic kits (antibody- or primer-based) for monitoring GPR183 expression in clinical or research settings
- Novel immuno-oncology therapeutics targeting GPR183 signaling as a monotherapy or adjunct to existing cancer treatments
Advantages
- Enables prediction of immune-related adverse event risk before or during immunotherapy, supporting proactive clinical management- Distinguishes toxicity-associated immune positioning (B cells) from tumor-associated immunosuppressive positioning (Tregs), allowing compartment-specific intervention
- Offers a strategy to reduce immune-mediated toxicity without broadly suppressing anti-tumor immune activity
- Compatible with multiple modulator formats (small molecules, antibodies, nucleic acid-based agents), providing flexibility in therapeutic design
- Applicable across a broad range of solid and hematological cancers and multiple immunotherapy modalities