Modulating the localization and persistence of microbial neoantigen vaccine vectors to enhance therapeutic efficacy

PROJECT SUMMARY The development of neoantigen cancer vaccines is transforming cancer immunotherapy – providing an approach to stimulate pre-existing and de novo anti-tumor T cell responses. These vaccines are designed to introduce tumor-specific neoantigens to activate the immune system, and can be amplified through tumor lysis–mediated epitope spreading. The focus of this project is to improve the therapeutic efficacy and safety of microbial neoantigen vaccines by modulating both their localization and persistence within the tumor microenvironment. Microbial vectors, such as E. coli Nissle 1917, have the natural ability to target hypoxic, immunosuppressed regions within tumors and deliver encoded neoantigens to elicit strong T cell responses. However, for these vaccines to be most effective, it is critical to control where and for how long bacteria persist in the body, as this impacts both their therapeutic effectiveness and safety profile. This proposal has three key objectives. First, it aims to explore how bacterial localization within tumors affects immune responses and overall therapeutic outcome. By understanding where bacterial vectors deliver encoded cargo – whether in tumor or non-tumor tissues – and the impact this has on immune activation, this project will provide insights that can improve cancer vaccine design. Second, these studies will investigate how bacterial persistence influences the strength and specificity of neoantigen-driven T cell responses. By regulating the duration of bacterial survival within the tumor microenvironment, this project seeks to balance the delivery of neoantigens with safety concerns. Third, this project will explore the use of inhalation-based delivery of microbial vaccines in a lung metastasis model. This alternative to intravenous delivery could offer a more targeted and safer approach, particularly for lung metastases, where treatment options are currently limited. This research addresses significant gaps in current cancer therapies, particularly for hard-to-treat cancers such as metastatic melanoma and lung metastases. Existing treatments are often insufficient, and many patients experience relapses or develop resistance to immunotherapies. By fine-tuning the location, persistence, and delivery method of microbial neoantigen vaccines, this project aims to create a safer, more effective cancer vaccination approach that could reduce off-target effects and improve patient outcomes. If successful, this work could lead to significant advancements, moving these treatments closer to clinical application.