PHASE I THERAPEUTIC AWARD - DEVELOPING SPLIT, CONDITIONALLY ACTIVE PEPTIDOMIMETICS OF IL-12 FOR THE TREATMENT OF RARE PEDIATRIC DIPG

Diffuse intrinsic pontine glioma (DIPG) is a rare, universally fatal childhood brainstem tumor, striking about 150-300 children in the US with a median survival of only 9-11 months. For 50 years, clinical trials in DIPG have been an abject failure; however, recently GD2-CAR-T therapy has shown promise in small DIPG clinical studies. A new paradigm for the treatment of DIPG is proposed using tumor-targeted mimics of a powerful immune stimulating cytokine IL-12, naturally found in the body. As a therapeutic, IL-12 bridges innate and adaptive immunity in human clinical trials but severe systemic toxicities limit the ability to achieve maximum benefit. This proposal radically engineers IL-12 so its biological activity is conditional to binding GD2 uniquely expressed on DIPG tumors. Instead of IL-12 protein, we use high content screening of macrocyclic peptidomimetic libraries containing 10^14 compounds to create completely new compounds that mimic IL-12, bioactivity, allowing precise chemistry-based tools to 1) conditionally activate IL-12R signaling upon GD2-binding (creating an AND gate), 2) minimize systemic exposure via tunable pharmacokinetics and 3) increase tumor penetration by minimizing molecular weight. Finally, a synthetic targeted IL-12 mimic sets the stage for future scalable manufacture that increases accessibility of immunotherapy to more DIPG patients.