Engineering Gut Bacterial Phase Variation to Synergize with Immunotherapy in Melanoma Patients

Cancer immunotherapy has transformed oncology, offering new hope to patients with advanced cancers such as melanoma. However, approximately 40% of melanoma patients do not respond to current immunotherapies, highlighting the urgent need for predictive biomarkers and therapies that can increase the response and convert “non-responder” patients into “responders”. Emerging evidence indicates that the functionality of the gut microbiota plays a critical role in modulating immune responses. A common mechanism that controls bacterial functionalities is genomic DNA inversions, regulating gene expression in a phase-variable manner. This project aims to harness such gut bacterial functional plasticity to enhance immunotherapy outcomes in melanoma patients applying a dual approach: (1) developing a non-invasive quantitative PCR-based diagnostic tool to identify potential responders; and (2) engineering gut bacteria in their immune-activating phase to activate the immune system and synergize with immunotherapy. The diagnostic tool will be validated on DNA from human stool samples, assessing its sensitivity, specificity, and predictive accuracy. The genetically engineered bacteria will be tested in melanoma mouse models, evaluating their impact on tumor regression, immune activation, and survival rates. The project also includes comprehensive market, IP, and business strategy analyses to ensure successful commercialization. If successful, this innovation will provide clinicians with a reliable method for patient stratification and offer a novel therapeutic approach to enhance immunotherapy responses, improving outcomes for patients who currently have limited treatment options.