Preclinical Evaluation of Convection-Enhanced Delivery of Gd2- Directed Thermosensitive Magnetic Immunoliposomes Carrying Irinotecan and Demethylase Inhibitors to Treat Pediatric Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor with a median survival of approximately 10 months. Recent results have identified a somatic mutation in the H3F3A gene, resulting in replacement of lysine 27 by methionine in its encoded histone H3.3 protein (H3.3-K27M) that occurs primarily in DIPGs. However, translations to improvement in clinical outcomes have yet to materialize. To date, there has been little target exploration for immunotherapy applications in DIPG. Herein we propose a preclinical study of monoclonal antibodies(mAbs)-bearing thermosensitive magnetic liposomes targeting the disialoganglioside GD2 as an immunochemotherapy in patient-derived orthotopic xenograft models of Histone 3 K27M (H3K27M) mutated DIPG. The liposomes will encapsulate chemotherapeutic agents, CPT-11, a specific H3K27 demethylase inhibitor (GSK J4), and a HDAC inhibitor (Panobinostat), which together showed synergistic therapeutic effect in recent DIPG studies. GD2 is highly and uniformly expressed in patient-derived H3K27M DIPG cultures, and in vitro assays demonstrated substantial target-dependent complement and target cell killing by CDC (complement dependent cytotoxicity) and ADCC (antibodies dependent cell cytotoxicity). H3 WT pediatric high-grade gliomas (HGGs) do not express significant levels of GD2, and the H3K27M mutation is associated with increased synthesis of ganglioside pathway synthesis enzymes, suggesting expression of the GD2 antigen is driven by H3K27M-induced transcriptional dysregulation. To design the most optimal route bypassing the blood brain barrier, single-dose convection enhanced delivery (CED) administration, or intravenous administration of GD2-directed immunoliposomes respectively in multiple orthotopic xenograft models of DIPG will be conducted to evaluate antitumor efficacy within a 4-week period of administration compared to a CD19-directed immunoliposomes control cohort. Our preliminary CED results revealed the GD2 immunoliposomes was precisely delivered to the brainstem tumor according to the fluorescence distribution. In contrast, very little or no fluorescence was detected in normal brain adjacent to the tumor, indicating the immunoliposomes precisely target DIPG tumor by GD2 mAbs. Alternative magnetic filed (AMF) will be used to trigger drug release from thermosensitive magnetic lipsomesoems from increasing the temperature to 42 o C. Preclinical animal treatment response will be observed by in vivo imaging system (IVIS), and treatment-associated toxicity will be closely monitored during the period of immunoliposomes administration. If these results are predictive of human response, GD2-directed immunochemotherapy could have a transformative impact upon DIPG outcomes.

Project ID:PC10708-0732
External Project ID:MOST107-2314-B182-020