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

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Maximizing effects of current cytotoxic and immune therapies without increasing acute toxicity and complications would significantly enhance options for certain pediatric population and adult patients with soft tissue tumors. In particular, children with metastatic or recurrent solid tumors, su8ch as sarcoma, 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 novel drug-device combination with untested potential applications for 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 with drug delivery via low temperature-sensitive liposomes (LTLD) nanoparticles have the potential to change cancer treatment paradigms by systematically overcoming the primary limits of current therapies for solid tumors. These include insufficient local 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 threshold 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 nanoparticulate chemotherapeutic agents directly at/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, or allowing immunomodulation in an image-guided and targeted fashion. 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, once begun. 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 resistance 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 systemic abscopal impact. The proposed treatments in this research should change tumor growth, metabolism and oxygenation both through direct cytotoxicity as well as 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 begin to address the clinical challenges posed by advanced local disease through a robust bench-to-bedside pathway that combines the strengths of the NIH intramural CIO and NCI POB and CNMC extramural teams. The team has successfully treated with MR-HIFU the first pediatric patients in the US with benign solid tumors. We first proved and evaluated 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 successfully evaluated 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 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, deployed at the NIH Clinical Center.