Bench to Bedside: Non-invasive Treatment of Tumors in Children

从实验室到临床：儿童肿瘤的无创治疗

• 批准号: 10262659
• 负责人: Bradford Wood
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262659
• 关键词: Abscopal effect; Acoustics; Address; Adult; Aftercare; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antineoplastic Agents; Benign; Biomedical Engineering; Cell Maturation; Cells; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Conventional Surgery; Cytotoxic Chemotherapy; Deposition; Development; Devices; Disease; Disease Progression; Dose; Down-Regulation; Doxorubicin; Drug Combinations; Drug Delivery Systems; Drug Exposure; Equilibrium; Extramural Activities; Focused Ultrasound Therapy; Geometry; Goals; Heat shock proteins; Heating; High temperature of physical object; Hyperthermia; Hypoxia; Immune; Immune Evasion; Immune Tolerance; Immune response; Immunologic Adjuvants; Immunologic Markers; Immunologic Surveillance; Immunologics; Immunooncology; Immunotherapy; Induced Hyperthermia; Inflammatory; Intravenous; Investigation; Ionizing radiation; Learning; Lesion; Liposomal Doxorubicin; Liposomes; Local Therapy; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Mediating; Metabolism; Methods; Modality; Modeling; Neoplasm Metastasis; Nerve; Pathway interactions; Patients; Pediatric Neoplasm; Perfusion; Pharmaceutical Preparations; Phase; Physics; Physiologic pulse; Population; Pre-Clinical Model; Process; Protein Family; Radiofrequency Interstitial Ablation; Reaction; Recurrence; Recurrent Malignant Neoplasm; Refractory; Regulatory T-Lymphocyte; Relapse; Research; Risk; Safety; Science; Serum Markers; Signal Transduction; Site; Soft Tissue Neoplasms; Solid Neoplasm; Specificity; Stress; Systemic Therapy; T cell response; T-Lymphocyte; Techniques; Technology; Temperature; Therapeutic Agents; Thermal Ablation Therapy; Time; Tissues; Toxic effect; Translating; Treatment Failure; Tumor Antigens; United States National Institutes of Health; acute toxicity; adaptive immune response; angiogenesis; bench to bedside; cancer imaging; cancer therapy; checkpoint inhibition; chemotherapeutic agent; chemotherapy; cold temperature; cytotoxicity; early phase clinical trial; experience; fight against; first-in-human; hyperthermia treatment; image guided; image guided intervention; immune resistance; immunogenic cell death; immunoregulation; improved; model development; nanoparticle; nanoparticle drug; novel; novel therapeutics; objective response rate; outcome forecast; pediatric patients; pre-clinical; pre-clinical research; preclinical study; prevent; protein complex; response; therapy outcome; trafficking; tumor; tumor growth; uptake; young adult

Maximizing effects of current cytotoxic and immune therapies without increasing acute toxicity and complications would significantly benefit the pediatric population with soft tissue tumors. In particular, children with metastatic or recurrent solid tumors, continue to experience unacceptably poor prognosis. Progressive intensification of therapy may result in substantial acute toxicity and effects on the growing bodies of children. Clinicians must critically balance the risk of toxicities against the risk of tumor recurrence from inadequate treatment as even small reductions in dose can have negative impact on anti-cancer drug efficiency. This bench-to-bedside translational proposal focuses on performing the pre-clinical and clinical research required for introduction of a principally novel drug-device combination with great promise to the fight against a wide range of solid tumors in children, with potential wide applicability to adult cancer treatment as well. Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) and the combination of this technology with drug delivery via low temperature-sensitive liposomes (LTLD) have the potential to change cancer treatment paradigms by systematically overcoming the primary limits of current therapies for solid tumors. These include insufficient drug delivery, lack of treatment specificity, and image guided spatial control over local therapy and inherent risks thereof. MR-HIFU is entirely non-invasive, does not require the use of ionizing radiation, and its use addresses the issue of therapy failure due to incomplete heating through precise image guidance, real-time temperature mapping, and spatially well-defined deposition of energy to maximize local chemotherapy delivery (often defining efficacy) and minimize systemic levels, which often define toxicities and risk. Mild hyperthermia (40 45 C, HT) modality alone using MR-HIFU has been shown to trigger intravascular release of chemotherapeutic agents directly in the site of the heated tumor in pre-clinical models. This strategy resulted in a 40-fold increase in local drug concentration compared to free drug in pre-clinical studies, while minimizing systemic exposure. For doxorubicin, dose intensity is an important determinant of response and survival. Therefore maximizing local drug concentration in the targeted lesion is a goal of paramount clinical importance. Ability to deliver drug specifically to a heated region may allow for treatment of regions that are not accessible to conventional surgery and thermal ablation, potentially sparing critical nerves and vasculature. We recently demonstrated that preventing drug washout by shutting down perfusion at the end of HT results in even greater drug exposure of the target, resulting in up to 40% greater drug uptake than LTLD-HT alone. We propose to combine high temperature ablative and vasculature-disrupting pulses (e.g. 50C, 20 seconds) to achieve this effect. The combination of LTLD and MR-HIFU would be a first in human application in a clinical setting. In addition to improving local delivery of therapeutic agents, immune-adjuvant effects of HIFU enhance antigen availability, antigen presenting cell maturation, T-cell trafficking, T-cell priming, and downregulation of the regulatory T cells and immune resistant pathways. Specifically, HIFU also potentiates the effects of checkpoint inhibition and can convert an immune cold tumor into an immune hot one. Tissue and serum markers of immunomodulation will be assessed in the clinical trial. Similar to radiofrequency ablation, HIFU can cause marked inflammatory reactions with an influx of immune cells along with development of circulating T cells activated specifically toward tumor antigens. However, Immunomodulatory effects of HIFU in influencing the balance between immune surveillance and immune evasion has not been fully explored. This balance may be particularly crucial in the setting of development and progression of metastases as well as local progression after treatment. Therefore, further investigation is warranted to decipher the potential immunologic impact beyond physical effect as a stand-alone treatment. Such effects could augment the systemic T cell response following a local HIFU treatment, resulting in better local and abscopal impact. The proposed treatments in this research will change tumor growth, metabolism and oxygenation both through direct cytotoxicity and indirectly. Indirect responses include various cellular mechanisms such as the response to sub-lethal heating via the Heat Shock Protein (HSP) family and complex processes such as angiogenesis, DAMPs, PAMPs, and hypoxia and stress signals. The effects controlled by cellular responses to heat and oxygenation impact therapeutic outcome and they may be used to plan therapy, or measure post-treatment disease progression. Learning to control and modulate this balance may be critical to development of effective systemic therapy in patients with metastatic and locally recurrent cancer. In this study, we will address the clinical challenges posed by advanced local disease through a robust bench-to-bedside pathway that combines the strengths of the NIH intramural and CNMC extramural teams. The team has successfully treated with MR-HIFU the first pediatric patients in the US with benign solid tumors. We will first evaluate the relative ability of the LTLD with HT followed by high temperature pulse (HT+) to improve homogeneity and overall levels of drug delivery in a preclinical VX2 tumor model. In addition to drug delivery, we will evaluate the ability to heat the entire target with HT, as well as to deliver the high temperature pulse over the entire tumor with MR-HIFU. The effects of therapy on enhancing host immune response will also be evaluated using novel methods developed at the NIH. We will evaluate the safety and clinical benefit of LTLD-HT+ in an early phase clinical trial for refractory solid tumors in children and young adults. This nanoparticle drug plus HIFU and hyperthermia device will be image guided by MRI, in a sophisticated symphony of biomedical engineering, acoustic physics, immuno-oncology and imaging science.

在不增加急性毒性和并发症的情况下，当前细胞毒性和免疫疗法的影响最大化将显着通过软组织肿瘤有益于小儿种群。特别是，具有转移性或复发性实体瘤的儿童继续经历不可接受的预后不良。治疗的逐步加强可能会导致大量的急性毒性和对成长中儿童身体的影响。临床医生必须在毒性的风险与肿瘤复发的风险不足的风险中保持关键水平，因为即使剂量的少量减​​少也会对抗癌药物效率产生负面影响。 这项基准对床位的翻译提案着重于进行临床前和临床研究，以引入主要新颖的药物脱发组合，并有很大的希望，可以与儿童的广泛实体瘤作斗争，并潜在地适用于成人癌症治疗。 磁共振引导的高强度聚焦超声（MR-HIFU）以及通过低温敏感脂质体（LTLD）将该技术与药物递送的组合有可能通过系统地克服实体瘤当前疗法的主要限制来改变癌症治疗范例。这些包括药物输送不足，缺乏治疗特异性以及对局部治疗的图像指导性控制及其固有风险。 Hifu先生完全没有侵入性，不需要使用电离辐射，并且其使用解决了由于通过精确的图像指导，实时温度映射和空间定义明确的能量沉积以最大程度地降低局部化学疗法的效率（通常定义效率），并且通常将系统性降低，并且通常将系统性化降低，并且通常将系统性降低，并且通常将系统性降低，并且通常会降低系统性的损害，因此可以解决治疗失败的问题。 在临床前模型中，仅使用MR-HIFU的轻度高温（40 45 C，HT）单独使用MR-HIFU直接在加热肿瘤部位引发血管内释放。与临床前研究中的自由药物相比，该策略使局部药物浓度增加了40倍，同时最大程度地减少了全身暴露。对于阿霉素，剂量强度是反应和存活的重要决定因素。因此，在靶向病变中最大化局部药物浓度是最重要的临床重要性的目标。能够专门为加热区域输送药物的能力可以治疗常规手术和热消融无法使用的区域，并可能避免关键神经和脉管系统。 我们最近证明，通过在HT结束时关闭灌注来防止药物冲洗会导致靶标的药物暴露更大，从而导致与单独使用LTLD-HT相比，药物吸收高达40％。我们建议将高温烧蚀和脉管系统破裂的脉冲（例如50C，20秒）结合起来，以实现此效果。 LTLD和MR-HIFU的组合将是临床环境中人类应用的第一组。 除了改善治疗剂的局部输送外，HIFU的免疫辅助作用可增强抗原的可用性，抗原呈现细胞成熟，T细胞运输，T细胞启动以及调节性T细胞的下调和免疫抗性途径。具体而言，HIFU还增强了检查点抑制的影响，并可以将免疫冷肿瘤转化为免疫热肿瘤。免疫调节的组织和血清标记将在临床试验中评估。 与射频消融相似，HIFU可能会引起与免疫细胞涌入的明显炎症反应，以及循环T细胞的发展，该T细胞的发育是特异性地激活了肿瘤抗原。然而，HIFU在影响免疫监测和免疫逃避之间平衡的免疫调节作用尚未得到充分探索。这种平衡在转移和治疗后局部进展的情况下可能尤为重要。因此，有必要进行进一步的研究，以破译作为独立治疗的物理效应的潜在免疫学影响。这种影响可以在局部HIFU治疗后增加全身T细胞的反应，从而产生更好的局部和潜在影响。 这项研究中提出的治疗方法将通过直接的细胞毒性和间接地改变肿瘤的生长，代谢和氧合。间接反应包括各种细胞机制，例如通过热休克蛋白（HSP）家族（HSP）家族和复杂过程（例如血管生成，潮湿，PAMP，低氧和应激信号）对亚致死加热的反应。细胞对热和氧合的反应控制的影响影响治疗结果，它们可用于计划治疗或测量治疗后疾病的进展。学习控制和调节这种平衡可能对于转移性和局部复发性癌症患者的有效全身治疗的发展至关重要。 在这项研究中，我们将通过强大的基准对居民途径来解决局部疾病提出的临床挑战，该途径结合了NIH壁内和CNMC外壁外团队的优势。该团队已成功地用hifu治疗了美国最早患有良性实体瘤的儿科患者。我们将首先评估LTLD与HT的相对能力，然后评估高温脉冲（HT+）在临床前VX2肿瘤模型中提高同质性和总体药物递送水平的相对能力。除了药物输送外，我们还将评估用HT加热整个靶的能力，并通过MR-HIFU在整个肿瘤上递送高温脉冲。还将使用NIH开发的新方法评估治疗对增强宿主免疫反应的影响。我们将在早期临床试验中评估LTLD-HT+在儿童和年轻人难治性实体瘤的安全性和临床益处。 这种纳米颗粒药以及HIFU和高温设备将以MRI为指导，在生物医学工程，声学物理学，免疫肿瘤学和成像科学的复杂交响曲中。