Program 1: Gene Therapy for GBM Using AAV
In our AAV (adeno-associated virus) project, we’re exploring the potential of AAV, a non-pathogenic and replication-deficient virus, for gene therapy in glioblastoma (GBM). AAVs are renowned in both pre-clinical and clinical settings for their ability to deliver genes with precision, showing minimal off-target effects when equipped with tissue-specific promoters. However, the challenge lies in effectively targeting GBM cancer cells using AAV vectors.
Our approach involves screening a combinational AAV capsid library through a direct evolution process. The goal is to identify highly specific vectors that can target a wide range of human glioblastoma stem cells (GSCs), focusing on both slow- and fast-cycling GSCs. We aim to discover novel AAV variants capable of efficiently expressing shRNA to target core GSC master regulators. This project holds promise for progressing into clinical development, potentially offering a new avenue for GBM treatment.
Program 2: In situ vaccination of brain cancer
PROJECT 1: Immunotherapy by Transdifferentiation
(Adapted from Liu et al, Cancer Immunol Res, 2024)
Current therapeutic options for GBM are limited, with long-term survival being a rarity. Immunotherapies, especially those involving dendritic cells (DCs), have shown promise but are hindered by challenges such as poor DC migration to brain tumors and the high costs of cell-based therapies. This project’s primary goal is to transform GBM cells into DCs, thereby circumventing these limitations. Enabled by the capabilities of NETZEN, our approach focuses on identifying master fate factors essential for this transformation.
PROJECT 2: TTFields-based in-situ vaccination of brain tumor
This graphic illustrates a proposed mechanism for enhancing anti-cancer immune response in glioblastoma (GBM) using Tumor Treating Fields (TTFields). TTFields activate the AIM2/cGAS-STING inflammasomes, leading to a complete in situ immunizing effect. This drives Type I interferon (T1IFN) signaling, resulting in dendritic cell (DC) activation and T cell activation. Together with anti-PD-1 immunotherapy, this approach promotes T cell clonal replacement and selection, ultimately improving survival outcomes in GBM patients.
PROJECT 3: In-situ vaccination by Laser Interstitial Thermal Therapy (LITT)
(Adapted from Leuthardt, E, et al. PlosOne 2016)
Program 3: Targeting Tumor Dormancy in Metastatic Breast Cancer
Despite significant advances in breast cancer treatment, including novel therapies, metastatic triple-negative and endocrine-resistant breast cancer continue to pose significant clinical challenges. Our project is centered on a potent new strategy to eliminate minimal residual disease in cancer patients following multimodal treatment.
We’re focusing on the role of disseminated tumor cells (DTCs) found in secondary organs like the bone marrow, which are a major factor in treatment failure for breast cancer patients. Clearing these DTCs from the bone marrow is crucial for improving overall survival. Our strategy targets the growth factors that sustain DTC survival in distant tissues. We are currently conducting a Phase I/II clinical trial, named EMPOWER, to address this high-risk residual disease, hoping to bring a transformative change in the treatment of breast cancer.
Other Research Projects: