Baculovirus-Based Minimally Invasive Therapy for Head and Neck Squamous Cell Carcinoma

About This Grant

PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium of the oral cavity, pharynx, and larynx. Given the critical functional and structural roles of these tissues, preserving their integrity during cancer treatment is essential. However, approximately 50% of patients undergoing current standard treatments experience local recurrence, largely due to the presence of a substantial precancerous field near the tumor margin. This underscores an urgent need for effective, minimally invasive therapies for HNSCC. This project seeks to develop an in vivo gene editing system leveraging baculoviral vectors for HNSCC treatment. Advances in CRISPR gene editing have revolutionized the potential to treat intractable genetic diseases by enabling precise modifications of specific genomic loci. Unlike traditional gene therapy, RNA-guided CRISPR technology can target nearly any gene and simultaneously modify multiple targets. Nonetheless, the therapeutic application of in vivo CRISPR remains hindered by off-target effects, which risk introducing harmful mutations in normal tissues. Our proposed system utilizes baculoviral vectors (BVs) derived from an insect virus, which are highly biocompatible and capable of efficiently transducing a wide range of mammalian cells, including dormant stem cells. Importantly, BVs have a large DNA packaging capacity, allowing them to carry CRISPR components along with genetic regulatory elements. Preliminary studies in our lab demonstrated that BVs conjugated with magnetic nanoparticles can be locally activated via an external magnetic device, and BV-mediated Pdl1 disruption significantly suppressed tumor growth and improved survival in a mouse syngeneic colon cancer model. Building on this success, we propose integrating nanoparticle-mediated viral transduction with a microRNA (miR)-based cell classifier to achieve precise, cell-specific gene disruptions. Our central hypothesis is that combining nanotechnology with synthetic biology circuits will enable BVs to target cancer cells efficiently and specifically, offering a minimally invasive therapy for HNSCC with cellular precision. By disrupting oncogenes and immune checkpoints, this approach aims to eliminate cancer cells and elicit a durable immune response to prevent recurrence. The study will employ clinically relevant models, including two mouse syngeneic oral cancer models and a patient-derived organotypic tumor slice culture model. If successful, this research will pave the way for a novel therapeutic strategy that delivers precise, durable, and minimally invasive treatment for HNSCC patients.