Multimodal MRI for guiding bacterial cancer therapy

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In response to the specific FOA that explicitly focuses on microbial-based cancer therapy (Bugs as Drugs), we propose to develop reliable multimodal MRI guidance to improve the efficacy and safety of bacterial cancer therapies for treating poorly vascularized, hypoxic tumors, where conventional cancer therapies are inadequate. Even though some have managed to reach clinical trial status, the development of microbial-based therapeutics for solid tumors has been long hindered by inconsistent results. Researchers in the field of microbial-based therapeutics have a major problem of inadequate and inconsistent means of guiding, monitoring, and assessing results of administered microbial therapy. Currently, the patient recruitment criteria for bacterial therapy are not specific and suitability is mainly judged by tumor size. The surrogate markers for bacterial germination/infection are radiological signs of tumor destruction and/or clinical signs and symptoms of systemic infection. There is an urgent need for developing noninvasive imaging tools that can identify patients who likely respond (stratification) by tumor hypoxia and real-time, quantitively measure the germination and proliferation of therapeutic bacteria in target tumors. To address these unmet needs, we will develop and optimize two emerging imaging technologies in this study: a) bacteria-detecting Chemical Exchange Saturation Transfer (CEST) MRI method (namely bacCEST) to assess bacterial infection in the tumor, serving as a non-invasive means to monitor therapeutic effects and adjust the treatment plan, and b) Oxygen-Enhanced (OE) MRI to characterize tumor hypoxia and hence predict the tumors’ vulnerability to anaerobic bacteria. We hypothesize that that the efficacy and safety of bacterial treatment can be significantly improved using non-invasive, multimodal MRI methods that can characterize tumor hypoxia prior to treatment and monitor bacterial infection at early time points. We have strong preliminary data demonstrating the efficacy of C. novyi-NT and capabilities of advanced MRI technologies, and gathered a multidisciplinary team of oncologists and imaging experts to complete the following aims: 1) Establish bacteria-detecting bacCEST MRI as a surrogate marker for C. novyi-NT treatment, 2) Establish hypoxia- detecting OE MRI to stratify tumors and guide bacterial treatment, and 3) Establish multimodal MRI guidance to improve the efficacy and safety of bacterial cancer therapy. Successful completion of the proposed study will provide approaches for multimodal MRI guidance that can ultimately improve the success rate of cancer therapies using anaerobic bacteria, including but not limited to C. novyi-NT. This MRI platform technology, once translated to human scanners, will address an unmet need in bacterial treatment and can accelerate the development and clinical testing of bacterial therapies. It will also benefit other areas in medicine (e.g., infection medicine/sepsis), thereby pushing clinical capabilities forward.