Multimodal MRI for guiding bacterial cancer therapy

为了回应明确关注基于微生物的癌症治疗的特定FOA（错误即药物），我们 建议开发可靠的多模态MRI引导，以提高细菌性癌症的疗效和安全性 用于治疗血管化不良的缺氧肿瘤的治疗方法，其中常规癌症治疗是不充分的。 尽管有些药物已经进入临床试验阶段，但基于微生物的治疗方法的发展 长期以来一直受到不一致结果的阻碍。微生物领域的研究人员 治疗的主要问题是指导、监测和评估的手段不充分和不一致 微生物治疗的结果。目前，细菌治疗的患者招募标准不是 特异性和适用性主要根据肿瘤大小来判断。细菌萌发/感染的替代标志物 是肿瘤破坏的放射学征象和/或全身感染的临床征象和症状。有一个 迫切需要开发无创成像工具，以识别可能有反应的患者（分层） 通过肿瘤缺氧和实时定量测定治疗细菌在肿瘤中的萌发和增殖， 靶向肿瘤。为了解决这些未满足的需求，我们将开发和优化两种新兴的成像技术 在这项研究中：a）细菌检测化学交换饱和转移（CEST）MRI方法（即 bacCEST）来评估肿瘤中的细菌感染，作为监测治疗的非侵入性手段。 B）氧增强（OE）MRI以表征肿瘤缺氧， 从而预测肿瘤对厌氧菌的脆弱性。我们假设， 使用非侵入性、多模式MRI方法可以显著改善细菌治疗， 在治疗前表征肿瘤缺氧并在早期时间点监测细菌感染。我们有强大 初步数据表明C. novyi-NT和先进MRI技术的能力，以及 聚集了一个由肿瘤学家和成像专家组成的多学科团队，以完成以下目标：1）建立 细菌检测bacCEST MRI作为C. novyi-NT治疗，2）建立缺氧- 检测OE MRI以分层肿瘤并指导细菌治疗，以及3）建立多模式MRI指导， 提高细菌治疗癌症的有效性和安全性。成功完成拟议的研究将 提供多模式MRI引导的方法，最终可以提高癌症的成功率 使用厌氧菌的疗法，包括但不限于C.诺维-NT这种MRI平台技术，一旦 翻译成人体扫描仪，将解决细菌治疗中未满足的需求，并可以加速 细菌疗法的开发和临床试验。它也将有利于医学的其他领域（例如，感染 医学/败血症），从而推动临床能力向前发展。

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.