THE PROBLEM

High-grade gliomas, including glioblastoma multiforme (GBM), are the most common primary central nervous system tumors with a high recurrence rate and extremely poor overall survival with a 5-year survival rate of approximately 5%. Despite success of CAR-T therapy in treating blood cancers, no CAR-T therapy has been approved for treating GBM. CAR-T therapy faces challenges such as off target effect and immunosuppressive tumor microenvironment (TME) where TGF-β signaling inhibits CAR-T activity. There is an urgent need for new therapeutic strategies to combat aggressive cancers.

THE SOLUTION

It has recently been discovered that GARP, a non-signaling receptor for docking and activation of latent TGF-β, is highly expressed in malignant cells in glioma, lung and breast cancers, and activated regulatory T cells in the TME. GARP-mediated activation of latent TGF-β, and subsequent TGF-β signaling, bolsters Treg responses and dampens the inflammatory anti-tumor immune response. Given its expression in both cancer cells and cancer -promoting Tregs, GARP is a promising target for immunotherapy.

Dr. Zihai Li and team have generated a novel anti-GARP-chimeric antigen receptor therapy that targets tumor cells and activated Tregs, but not platelets. Anti-GARP CAR-T therapy overcomes immune suppression in the TME by selectively depleting activated GARP+ Tregs and targeting GARP+ tumor cells. This GARP-targeting therapy has demonstrated high efficacy and specificity without significant toxicity in multiple preclinical models of high-grade glioma in mice, and a Phase 1 clinical trial is underway.

APPLICATIONS

• Monotherapy for GARP+ cancers, including high-grade glioma
• Combination therapy with ICB, TIL therapy, or other CAR-T therapies to improve treatment outcome of high-grade glioma, and other cancers

ADVANTAGES

• Dual action: anti-GARP CAR-T therapy mediates 1) direct killing of GARP+ tumor cells and 2) immunomodulation of Tregs in the TME
• Highly specific cytotoxicity: potent cytotoxicity against GARP+ targets with minimal off-target effects, sparing GARP-negative cells and resting Treg populations to reduce risk of adverse effects and autoimmunity
• Unique and versatile: first CAR-T therapy selectively targets Tregs in the TME, with potential applicability across multiple cancer types
• Demonstrated safety profile to enable Phase 1 clinical trial

Seeking opportunities for out-licensing, co-development, and collaboration