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最大限度地发挥当前细胞毒性和免疫疗法的作用将使患有软组织肿瘤的儿科人群受益匪浅。特别是患有转移性或复发性实体瘤的儿童，继续经历令人难以接受的不良预后。逐渐强化治疗可能会导致严重的急性毒性并对儿童成长中的身体产生影响。临床医生必须严格平衡毒性风险与治疗不充分导致肿瘤复发的风险，因为即使剂量小幅减少也会对抗癌药物的功效产生负面影响。 这项从实验室到临床的转化提案侧重于进行临床前和临床研究，以引入一种主要新颖的药物设备组合，该组合有望对抗儿童中的各种实体瘤，并具有广泛的适用性成人癌症治疗也是如此。 磁共振引导的高强度聚焦超声（MR-HIFU）以及该技术与低温敏感脂质体（LTLD）药物输送的结合有可能通过系统地克服当前实体疗法的主要限制来改变癌症治疗模式。肿瘤。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引导空间控制及其固有风险。 MR-HIFU 完全是非侵入性的，不需要使用电离辐射，它的使用通过精确的图像引导、实时温度测绘和空间明确的能量沉积解决了由于加热不完全而导致的治疗失败的问题最大化局部化疗递送（通常决定疗效）并最小化全身水平，这通常决定毒性和风险。 在临床前模型中，仅使用 MR-HIFU 的轻度热疗（40°C 45°C，HT）模式已被证明可以直接在加热肿瘤部位触发化疗药物的血管内释放。与临床前研究中的游离药物相比，该策略使局部药物浓度增加了 40 倍，同时最大限度地减少了全身暴露。对于阿霉素，剂量强度是反应和生存的重要决定因素。因此，最大化目标病变中的局部药物浓度是临床上最重要的目标。将药物专门输送到加热区域的能力可能可以治疗传统手术和热消融无法到达的区域，从而可能保护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流失，会导致靶标的药物暴露量更大，从而导致药物吸收比单独的 LTLD-HT 高出 40%。我们建议结合高温消融和脉管系统破坏脉冲（例如 50°C，20 秒）来实现这种效果。 LTLD 和 MR-HIFU 的结合将是人类在临床环境中的首次应用。 除了改善治疗剂的局部递送外，HIFU 的免疫佐剂作用还增强抗原可用性、抗原呈递细胞成熟、T 细胞运输、T 细胞启动以及调节性 T 细胞和免疫抵抗途径的下调。具体来说，HIFU还增强了检查点抑制的效果，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志物将在临床试验中进行评估。 与射频消融类似，HIFU 会引起明显的炎症反应，免疫细胞大量涌入，并产生针对肿瘤抗原特异性激活的循环 T 细胞。然而，HIFU 在影响免疫监视和免疫逃避之间的平衡方面的免疫调节作用尚未得到充分探索。这种平衡对于转移的发生和进展以及治疗后的局部进展可能特别重要。因此，有必要进行进一步的研究，以解读作为独立治疗的物理效应之外的潜在免疫影响。这种效应可以增强局部 HIFU 治疗后的全身 T 细胞反应，从而产生更好的局部和远隔影响。 本研究提出的治疗方法将通过直接细胞毒性和间接改变肿瘤生长、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) 家族对亚致死加热的反应，以及血管生成、DAMP、PAMP 以及缺氧和应激信号等复杂过程。细胞对热和氧合反应控制的效应影响治疗结果，它们可用于计划治疗或测量治疗后疾病进展。学会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开发有效的全身治疗至关重要。 在这项研究中，我们将通过结合 NIH 校内和 CNMC 校外团队优势的稳健的从实验室到临床的途径，解决晚期局部疾病带来的临床挑战。该团队已成功利用 MR-HIFU 治疗了美国首例患有良性实体瘤的儿科患者。我们将首先评估 LTLD 与 HT 结合高温脉冲 (HT+) 的相对能力，以提高临床前 VX2 肿瘤模型中药物输送的均匀性和总体水平。除了药物输送之外，我们还将评估用 HT 加热整个靶标的能力，以及用 MR-HIFU 在整个肿瘤上输送高温脉冲的能力。还将使用美国国立卫生研究院开发的新方法来评估治疗对增强宿主免疫反应的效果。我们将在儿童和年轻人难治性实体瘤的早期临床试验中评估 LTLD-HT+ 的安全性和临床益处。 这种纳米颗粒药物加上 HIFU 和热疗装置将由 MRI 进行图像引导，形成生物医学工程、声学物理学、免疫肿瘤学和成像科学的复杂交响乐。