Designer EcN for treatment of solid tumors

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Current modalities for the treatment of solid tumors include surgical resection, chemotherapy, and radiation, approaches that often are not sufficient to lead to cure and are generally associated with numerous side effects. Immunotherapy based interventions, including immunostimulatory monoclonal antibodies that block immune checkpoints, are revolutionizing the treatment of cancers as they provide a means to engage the patient’s own immune system to recognize and fight cancer. However, the systemic administration of these therapies is often associated with marked adverse reactions that can be very serious, particularly when multiple agents are used in combination. Novel means to target the efficient delivery of immunostimulatory molecules directly to tumors and neoplasmic deposits are needed. Interestingly, multiple bacterial species selectively colonize and proliferate to high titers in tumors where some like Salmonella and Clostridial species promote tumor regression and even clearance, at least in part by inducing host inflammatory responses. Attenuated versions of these bacteria are observed to effectively eradicate tumors in mouse models, but have shown limited success in human trials, likely because they are rapidly cleared from the systemic circulation such that the bacteria never reach and establish residence in the tumors. Interestingly, Nissle 1917 E. coli (EcN), a probiotic strain commonly used in the treatment of inflammatory bowel disease, also homes to and colonizes solid tumors. Yet, despite reaching titers as high as 1010 colony forming units of bacteria/gram of tumor, EcN induces no response. Here we propose to test variants of EcN capable of delivering immunostimulatory nanobodies that block that activity of immune checkpoint proteins directly into the microenvironment of solid tumors. We will then investigate the ability of these strains to promote tumor regression using a mouse model of melanoma. We will also conduct genome-wide transposon insertion screens to identify EcN determinants involved in the homing to and proliferation within solid tumors. It is our expectation that at the completion of this exploratory 2-year grant we will have proof-of-concept that the programmable immune-based bacteriotherapy we are developing has the potential to become a novel cancer therapeutics platform.