Probiotic neoantigen delivery vectors for precision cancer immunotherapy

Authors: Redenti et al.DOI: 10.1038/s41586-024-08033-4Central Idea: This study engineers a probiotic E. coli Nissle 1917 strain to deliver tumor-specific neoantigens, creating a potent in situ cancer vaccine. This engineered probiotic effectively stimulates anti-tumor immunity and controls or eliminates tumor growth in mouse models of colorectal cancer and melanoma.Key Concepts:Neoantigen-based vaccines: Neoantigens are tumor-specific mutations, making them ideal targets for immunotherapy. Existing neoantigen vaccine approaches have shown limited efficacy.Engineered E. coli vector: Researchers modified E. coli Nissle 1917 to enhance neoantigen production and delivery. Key modifications include removing cryptic plasmids and Lon/OmpT proteases, increasing phagocytosis susceptibility, and expressing listeriolysin O (LLO).Enhanced neoantigen production: Removing proteases and cryptic plasmids significantly boosted neoantigen expression within the bacteria.Improved antigen presentation: Increased phagocytosis and LLO expression enhanced neoantigen uptake and presentation by antigen-presenting cells (APCs), including MHC class I presentation via cytosolic delivery.Antitumor efficacy: The engineered E. coli vaccine elicited potent T cell responses, controlled tumor growth, and even eradicated tumors in both primary and metastatic tumor models. Intravenous administration proved effective, overcoming limitations of direct tumor injection.Systemic anti-tumor immunity: The vaccine induced systemic anti-tumor immunity, enabling the elimination of distant, untreated tumors.Favorable safety profile: The engineered bacteria exhibited reduced persistence in the bloodstream and minimal side effects compared to wild-type E. coli.Further Research/Unanswered Questions:Optimizing neoantigen selection: Refining neoantigen prediction algorithms and selection criteria for maximal immunogenicity.Clinical translation: Evaluating the safety and efficacy of this approach in human clinical trials.Combination therapies: Exploring the potential for synergy with other immunotherapies, such as checkpoint inhibitors or adoptive cell therapies.Long-term immunity and durability of response: Assessing the duration of anti-tumor immunity and the potential for tumor recurrence.Broader applicability: Testing the effectiveness against other cancer types.Manufacturing and scalability: Developing scalable manufacturing processes for clinical use.Microbiome impact: Investigating the long-term impact of the engineered bacteria on the gut microbiome.