Investigating the impact of tumor heterogeneity on sustained low dosage immunotherapy via a peritumoral immunotheranostic hydrogel

通过瘤周免疫治疗水凝胶研究肿瘤异质性对持续低剂量免疫治疗的影响

• 批准号: 1806007
• 负责人: Evan Scott
• 金额: $ 31.39万
• 依托单位: Northwestern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1806007&HistoricalAwards=false
• 关键词: Investigating; impact; tumor; heterogeneity; sustained

One of the most challenging aspects of cancer therapy is the uniqueness of each patient's disease, which can result in significant delays in effective diagnosis and treatment. This issue has become particularly critical for immunotherapy, which is therapy that uses therapeutics (drugs) to modify or enhance a patient's own immune system's ability to target and kill cancerous cells. Current immunotherapy methods use a series of high dose infusions, e.g., injections, of therapeutics into the blood circulation, which can severely disrupt the normal function of the immune system, resulting in harsh and often unpredictable side effects. For patients with melanoma (skin cancer) and other solid tumors, responses to treatment depend on both the unique variety of cells within the tumors and the therapeutics' ability to reach these cells and tissues. Thus, the research objective of this project is to engineer a customizable delivery system for investigating lower dose treatment strategies and for assessing the ability of different therapeutics to reach critical immune and cancer cells within tumors. The investigators will optimize and validate this system by measuring the accumulation of therapeutics within tumors and cells of two mouse models of melanoma, which are representative of two patient-specific disease differences due to different tumor structures. As opposed to a series of high dose infusions, these therapeutics will be administered in a controlled continuous fashion at low doses to investigate sustained and localized immunotherapy. This work may lead to a new immunotherapy treatment option with a lower number of unwanted side effects. The educational objective of this project is to expose undergraduate students and the public to the contributions of Biomedical Engineering in the field of cancer research. A Cancer Engineering course for undergraduates will be implemented to discuss fundamental engineering-based strategies to treat cancer. An accompanying website will be maintained by the students in the class that focuses on educating the public on how engineering concepts enhance strategies for cancer therapy.The goal of this project is to design and apply a novel system to investigate the impact of tumor heterogeneity on the pathophysiology of the tumor microenvironment during sustained low dosage immunomodulation. The project's first objective is to tailor filomicelle (FM)-hydrogels for the sustained peritumoral delivery of immunotheranostic (combined immunotherapy and diagnostics) micelles (MCs) and biologics. FM-hydrogels will be customized to function as a tool for 1) real time diagnostic assessment of tumor margin heterogeneity via magnetic resonance imaging ( MRI), enabled by a DyLight 650 and Gd (gadolinium) tagged FM-hydrogels; 2) the sustained low dosage delivery of an immunostimulant (IMQ (imiquimod)) to induce pro-inflammatory stimulation of myeloid-derived suppressor cells (MDSCs) and localized release of cytokine IL-12 from tumor resident dendritic cells (DCs) and 3) the sustained low dosage delivery of IL-12 directly by loading the IL-12 within polymersomes (PS ) that will be covalently retained within the FM-hydrogel. During in vitro studies, photo-oxidation will be used to trigger the cylinder-to-sphere, i.e., FM-to-MC, transition and release of PS payloads on demand. Studies were designed to test the hypothesis that both IMQ and Gd will transfer from the FM-hydrogels to released micelles during the cylinder-to-sphere transition and remain active. The project's second objective is to investigate the influence of in vivo localized and sustained delivery of immunotheranostic MCs and IL-12 to the microenvironment of clinically relevant heterogeneous solid tumors. Two melanoma mouse models (BRAF(V600E)/PTEN and B16F10) were strategically selected due to their significant differences in vascular development and presence of immunosuppressive cells within their microenvironments. The differences in lymphatic drainage will be mapped and compared to provide insight into how heterogeneity at the tumor margin can impact intratumoral targeting of therapeutics and the interactions between nanomaterials and immune cells critical to cancer immunotherapy will be examined. Studies were designed to test two hypotheses: 1) that differences in tumor heterogeneity between the models will impact lymphatic drainage and access of micelles to the tumor microenvironment and 2) that sustained low dosage delivery of immunomodulatory factors through the draining lymphatics of solid tumors will more efficiently inhibit tumor-induced immune suppression compared to high dosage intermittent injections. In addition to the potential to generate new approaches to treat and monitor changes within tumors, the platform developed may be useful for investigating sustained therapeutic dosing regimens, for assessing patient-specific vascular and lymphatic access to tumors for personalized cancer therapy and for investigating the impact of specific immunomodulatory factors on the progression and growth of solid tumors.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

癌症治疗最具挑战性的方面之一是每个患者的疾病的独特性，这可能导致有效诊断和治疗的重大延误。这个问题对免疫疗法来说尤其关键，免疫疗法是一种使用疗法(药物)来改变或增强患者自身免疫系统靶向并杀死癌细胞的能力的疗法。目前的免疫治疗方法使用一系列大剂量的治疗药物注入血液循环，这会严重扰乱免疫系统的正常功能，导致严重的副作用，通常是不可预测的。对于患有黑色素瘤(皮肤癌)和其他实体肿瘤的患者，对治疗的反应取决于肿瘤内独特的细胞种类以及治疗人员到达这些细胞和组织的能力。因此，该项目的研究目标是设计一种可定制的递送系统，用于研究较低剂量的治疗策略，并评估不同治疗药物到达肿瘤内关键免疫细胞和癌细胞的能力。研究人员将通过测量治疗药物在两种黑色素瘤小鼠模型的肿瘤和细胞内的积累来优化和验证这一系统，这两种黑色素瘤模型代表了由于肿瘤结构不同而导致的两种患者特定疾病的差异。与一系列高剂量输注相反，这些疗法将以受控的持续方式在低剂量下进行，以研究持续和局部的免疫疗法。这项工作可能导致一种新的免疫治疗选择，具有较少的不良副作用。这个项目的教育目标是让本科生和公众了解生物医学工程在癌症研究领域的贡献。将为本科生开设癌症工程学课程，讨论以工程学为基础的癌症治疗策略。课堂上的学生将维护一个附属的网站，重点教育公众工程概念如何增强癌症治疗策略。本项目的目标是设计和应用一种新的系统，以调查在持续低剂量免疫调节期间肿瘤异质性对肿瘤微环境的病理生理学的影响。该项目的第一个目标是量身定做丝状胶束(FM)水凝胶，用于持续地在瘤周输送免疫抗肿瘤药物(结合免疫治疗和诊断)胶束(MC)和生物制剂。FM-水凝胶将被定制为1)通过磁共振成像(MRI)对肿瘤边缘异质性进行实时诊断评估的工具，通过DyLight 650和Gd(Gd)标记的FM-水凝胶实现；2)持续低剂量的免疫刺激剂(ImQ(咪喹莫特))以诱导髓系来源的抑制细胞(MDSCs)的促炎刺激，并从肿瘤常驻树突状细胞(DC)中局部释放细胞因子IL-12；3)通过将IL-12加载到将共价保留在FM-水凝胶内的聚合体(PS)内，直接持续低剂量地输送IL-12。在体外研究中，光氧化将被用来触发圆柱体到球体，即FM到MC的转变，并根据需要释放PS有效载荷。研究的目的是验证这样的假设，即ImQ和Gd在柱体到球体的转变过程中都将从FM水凝胶转移到释放的胶束并保持活性。该项目的第二个目标是研究体内局部和持续递送免疫差异性MC和IL-12对临床相关的异质实体瘤微环境的影响。两种黑色素瘤小鼠模型(BRAF(V600E)/PTEN和B16F10)由于其血管发育和微环境中免疫抑制细胞的存在显著不同而被策略性地选择。将绘制和比较淋巴引流的差异，以深入了解肿瘤边缘的异质性如何影响治疗药物的肿瘤内靶向，并将检查对癌症免疫治疗至关重要的纳米材料和免疫细胞之间的相互作用。研究旨在验证两个假设：1)模型之间肿瘤异质性的差异将影响淋巴引流和胶束进入肿瘤微环境；2)通过实体肿瘤引流淋巴管持续低剂量输送免疫调节因子将比高剂量间歇注射更有效地抑制肿瘤诱导的免疫抑制。除了产生治疗和监测肿瘤内变化的新方法的潜力外，开发的平台可能有助于研究持续治疗剂量方案，评估患者特定的血管和淋巴进入肿瘤的个性化癌症治疗，以及调查特定免疫调节因素对实体肿瘤进展和生长的影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

An Injectable Hydrogel Platform for Sustained Delivery of Anti-inflammatory Nanocarriers and Induction of Regulatory T Cells in Atherosclerosis

• DOI: 10.3389/fbioe.2020.00542
• 发表时间: 2020-06
• 期刊: Frontiers in Bioengineering and Biotechnology
• 影响因子: 5.7
• 作者: Sijia Yi;Nicholas B. Karabin;Jennifer Zhu;Sharan Bobbala;Huijue Lyu;Sophia Li;Yugang Liu;Molly A Frey