Potential Of Radiotherapy Research Articles

Recent Trends and Potential of Radiotherapy in the Treatment of Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy characterized by advanced disease at diagnosis and a poor prognosis. Despite multimodal therapeutic approaches that include surgery, radiotherapy, and chemotherapy, an optimal treatment strategy remains elusive. Current developments in targeted therapies and immunotherapy offer promising avenues for improved outcomes, particularly for BRAF-mutant patients. However, challenges remain regarding overcoming drug resistance and developing effective treatments for BRAF-wild-type tumors. This comprehensive review examines the clinical and biological features of ATC, outlines the current standards of care, and discusses recent developments with a focus on the evolving role of radiotherapy. Moreover, it emphasizes the necessity of a multidisciplinary approach and highlights the urgent need for further research to better understand ATC pathogenesis and identify new therapeutic targets. Collaborative efforts, including large-scale clinical trials, are essential for translating these findings into improved patient outcomes.

Architecture, flexibility and performance of a special electron linac dedicated to Flash radiotherapy research: electronFlash with a triode gun of the centro pisano flash radiotherapy (CPFR)

The FLASH effect is a radiobiological phenomenon that has garnered considerable interest in the clinical field. Pre-clinical experimental studies have highlighted its potential to reduce side effects on healthy tissues while maintaining isoeffectiveness on tumor tissues, thus widening the therapeutic window and enhancing the effectiveness of radiotherapy. The FLASH effect is achieved through the administration of the complete therapeutic radiation dose within a brief time frame, shorter than 200 milliseconds, and, therefore, utilizing remarkably high average dose rates above at least 40 Gy/s. Despite its potential in radiotherapy, the radiobiological mechanisms governing this effect and its quantitative relationship with temporal parameters of the radiation beam, such as dose-rate, dose-per-pulse, and average dose-rate within the pulse, remain inadequately elucidated. A more profound comprehension of these underlying mechanisms is imperative to optimize the clinical application and translation of the FLASH effect into routine practice. Due to the aforementioned factors, the undertaking of quantitative radiobiological investigations becomes imperative, necessitating the utilization of sophisticated and adaptable apparatus capable of generating radiation beams with exceedingly high dose-rates and dose-per-pulse characteristics. This study presents a comprehensive account of the design and operational capabilities of a Linear Accelerator (LINAC) explicitly tailored for FLASH radiotherapy research purposes. Termed the “ElectronFlash” (EF) LINAC, this specialized system employs a low-energy configuration (7 and 9 MeV) and incorporates a triode gun. The EF LINAC is currently operational at the Centro Pisano FLASH Radiotherapy (CPFR) facility located in Pisa, Italy. Lastly, this study presents specific instances exemplifying the LINAC’s adaptability, enabling the execution of hitherto unprecedented experiments. By enabling independent variations of the temporal parameters of the radiation beam implicated in the FLASH effect, these experiments facilitate the acquisition of quantitative data concerning the effect’s dependence on these specific parameters. This novel approach hopefully contributes to a more comprehensive understanding of the FLASH effect, shedding light on its intricate radiobiological behavior and offering valuable insights for optimizing its clinical implementation.

Abstract 1663: Activation of STING in response to partial-tumor radiation exposure

Abstract Purpose: To determine whether STING activation is involved in partial volume radiation therapy. Background: The potential of radiotherapy (RT) to induce immune recognition of cancer cells is a growing topic of research. It has been suggested that partial volume irradiation used in GRID therapy/Lattice RT, a type of RT in which radiation does not cover the entire tumor intentionally but rather is spatially fractionated, sometimes induces an immune response. We previously showed that a single dose of radiation delivered to half of the tumor (50% RT) activated an anti-tumor immune response comparable to the response in a fully-irradiated tumor in the immunogenic 67NR murine tumor model (breast carcinoma) and in the less immunogenic and more radioresistant Lewis lung carcinoma (LLC) tumor model. We have also demonstrated that this immune response was due to the infiltration of CD8+ T cells along with an increased expression of ICAM adhesion molecules. Treatment with either anti-CD8 or anti-ICAM antibodies abrogated the hemi-RT response. Furthermore, a significant abscopal effect was observed after partial irradiation with a single dose of 10Gy in a bilateral 67NR tumors model. It has been shown that ionizing radiation can mediate antitumor immunity via the activation of the cytosolic DNA sensor cGAS/STING pathway. Therefore, in this study, we tested whether the hemi-irradiation-mediated immune response involves the cGAS/STING canonical pathway, or a non-canonical activation of STING, in the 67NR or LLC tumor models. It has been reported that STING can be activated, independently of cGAS, via non-canonical activation of STING, involving ATM and TRAF6, among other factors. Brief methods: We investigated 67NR murine orthotopic breast tumors in Balb/c mice and LLC cells injected in the flank of C57Bl/6, cGAS or STING KO mice. RT was delivered to 50% or 100% of the tumor volume using a 2X2 cm collimator on a microirradiator allowing precise irradiation. Tumors were collected at different time points post-RT and assessed for different measurements. Results: There is significant activation of the cGAS/STING pathway in the hemi-irradiated tumors as compared to control and to 100% exposed 67NR tumors. Interestingly, the increased expression of the cGAS/STING pathway was found in the hemi-irradiated tumor but, also in the non-irradiated part of the tumor. In the LLC model, a non-canonical activation of STING is involved. Using both cGAS and STING KO mice, we demonstrated that the partial exposure RT-mediated immune response is dependent on STING activation in the host while cGAS is dispensable. Conclusions: Identifying the upstream pathways responsible for STING activation in the partial RT-mediated immune response in different tumor types would improve this therapy and its potential combination with immune checkpoint blockade. Citation Format: Mickael Mathieu, Prerna R. Nepali, Sadna Budhu, Simon N. Powell, John L. Humm, Joseph O. Deasy, Adriana Haimovitz-Friedman. Activation of STING in response to partial-tumor radiation exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1663.

Efficient Heat Shock Response Affects Hyperthermia-Induced Radiosensitization in a Tumor Spheroid Control Probability Assay.

Simple SummaryResistance to therapy and subsequent relapse of the disease are common in patients with cancers in the head and neck region (HNSCC). Recent technological advancements have revitalized the concept of combining hyperthermia (HT) with radio(chemo)therapy for treating these patients. Heat inherently affects multiple cellular components and destroys protein structures, thereby influencing the DNA damage response. However, the plethora of adverse mechanisms in HT-induced radiosensitization is still not fully elucidated. We uniquely evaluated the radiosensitizing potential of HT in HNSCC cells using a sophisticated spheroid assay platform, which turned out as a powerful tool to compare different treatment modalities and gain new mechanistic insight. We show that HT disrupts vital cellular proteostasis and affects global stress response signaling. This triggers massive heat shock and proteotoxic stress responses contributing to the cancer cells’ protection against HT-induced radiosensitization. Selected molecules in this scenario may serve as new targets for combination with hyperthermia and radiotherapy.Hyperthermia (HT) combined with irradiation is a well-known concept to improve the curative potential of radiotherapy. Technological progress has opened new avenues for thermoradiotherapy, even for recurrent head and neck squamous cell carcinomas (HNSCC). Preclinical evaluation of the curative radiosensitizing potential of various HT regimens remains ethically, economically, and technically challenging. One key objective of our study was to refine an advanced 3-D assay setup for HT + RT research and treatment testing. For the first time, HT-induced radiosensitization was systematically examined in two differently radioresponsive HNSCC spheroid models using the unique in vitro “curative” analytical endpoint of spheroid control probability. We further investigated the cellular stress response mechanisms underlying the HT-related radiosensitization process with the aim to unravel the impact of HT-induced proteotoxic stress on the overall radioresponse. HT disrupted the proteome’s thermal stability, causing severe proteotoxic stress. It strongly enhanced radiation efficacy and affected paramount survival and stress response signaling networks. Transcriptomics, q-PCR, and western blotting data revealed that HT + RT co-treatment critically triggers the heat shock response (HSR). Pre-treatment with chemical chaperones intensified the radiosensitizing effect, thereby suppressing HT-induced Hsp27 expression. Our data suggest that HT-induced radiosensitization is adversely affected by the proteotoxic stress response. Hence, we propose the inhibition of particular heat shock proteins as a targeting strategy to improve the outcome of combinatorial HT + RT.

Pharmacological Ascorbate Promotes the Tumor Radiosensitization of Au@Pd Nanoparticles with Simultaneous Protection of Normal Tissues

Nanoradiosensitizers containing high-Z elements hold great potential in radiotherapy owing to the increasing energy deposition effect on X-ray irradiation. However, their potential clinical application is limited by the irradiation damage in nontarget tissues surrounding the tumor site, as well as the safety concerns for nanomaterials. Our findings demonstrate that pharmacological ascorbate displays a synergistic radiosensitizing effect in combination with nanoradiosensitizers. By engineering the Au@Pd core-shell nanostructures and precisely regulating their shell thickness, the obtained Au@Pd nanomaterials exhibit excellent ascorbate oxidase-like activity. Along with the accelerating generation of H2O2, pharmacological ascorbate significantly enhances the radiosensitizing effect of Au@Pd-PEG nanoparticles on both cancer cells and solid tumor. Interestingly, pharmacological ascorbate effectively protects normal tissues from X-ray-induced injury. The present work demonstrates that pharmacological ascorbate is an ideal agent for selectively improving the radiosensitizing effect of nanomaterials, providing a promising strategy to facilitate the clinical translation of nanoradiosensitizers.

Harnessing Radiation Effects on the Immune System: Balancing Acts

The potential of radiotherapy (RT) to induce immune recognition of cancer cells is a growing topic of research. It has been suggested that partial volume irradiation used in GRID therapy/Lattice RT, a type of RT in which radiation does not cover the entire tumor intentionally but rather is spatially fractionated, sometimes induces an immune response. The therapeutic benefits of RT may not be limited solely to the targeted volume, but also present systemic antitumor effects, called the abscopal effect. The next challenge of RT now is to balance and control this immune response in patients. Here, we review what is known about the impact of RT on the innate and adaptive immune response.

An oxidation responsive nano-radiosensitizer increases radiotherapy efficacy by remolding tumor vasculature.

As an excellent candidate material for nano-sensitizers, gold nanostructures have shown great potential in radiotherapy. Nevertheless, severe hypoxia and low accumulation of nanomedicine caused by poor perfusion at the tumor site have significantly reduced radiotherapy efficacy. Vascular normalization has gained attention owing to its ability to relieve hypoxia and increase perfusion. The synergistic therapy of tumor vascular normalization and radiotherapy has become a new option to increase anti-cancer efficacy. However, the commonly used strategy of suppressing a single growth factor to induce vascular normalization is limited by tumor compensatory effects. In this work, we developed a strategy to inhibit oxidative stress in tumors by generating chelating agents in response to hydrogen peroxide, thereby inhibiting multi-angiogenic factors simultaneously to normalize blood vessels. Concretely, sodium alginate (SA) reacted with 8-quinoline boric acid (QBA) to form SA-QBA. Then gold nanoparticles (Au NPs) were modified with SA-QBA to obtain Au@SA-QBA. The system was simple in structure and could generate 8HQ in response to H2O2in vitro to inhibit oxidative stress and reduce the expression of VEGF, bFGF, and Ang-2. In vivo, the perfusion unit (PU) increased by 78% after Au@SA-QBA treatment, and the coverage of pericytes increased by 32%, which in turn induced vascular normalization. In addition, blood routine and blood biochemical tests confirmed its good biocompatibility and 8HQ was not detected in the supernatant after homogenization of major organs. More importantly, after the synergistic treatment of vascular normalization and radiotherapy (4 Gy), the tumor growth inhibition rate was increased by 38.6% compared to the Au@SA-treated group with negligible side effects to normal tissues.

Optimal scheduling of the nanoparticle-mediated cancer photo-thermo-radiotherapy.

Maximal synergistic effect between photothermal therapy and radiotherapy (RT) may be achieved when the interval between these two modalities is optimal. In this study, we tried to determine the optimal schedule of the combined regime of RT and nano-photothermal therapy (NPTT), based on the cell cycle distribution and kinetics of cell death. To this end, alginate-coated iron oxide-gold core-shell nanoparticles (Fe3O4@Au/Alg NPs) were synthesized, characterized, and their photo-radio sensitization potency was evaluated on human nasopharyngeal cancer KB cells. Our results demonstrated that synthesized NPs have a good potential in radiotherapy and near-infrared (NIR) photothermal therapy. However, results from flow cytometry analysis indicated that a major portion of KB cells were accumulated in the most radiosensitive phases of cell cycle (G2/M) 24 h after NPTT. Moreover, the maximal synergistic anticancer efficacy (12.3% cell viability) was observed when RT was applied 24 h following the administration of NPTT (NPs [30 μg/mL, 4 h incubation time] + Laser [808 nm, 1 W/cm2, 5 min] + RT [6 Gy]). It is noteworthy that apoptosis was the dominant cell death pathway in the group of cells treated by combination of NPTT and RT. This highly synergistic anticancer efficacy provides a mechanistic basis for Fe3O4@Au/Alg NPs-mediated photothermal therapy combined with RT. Knowing such a basis is helpful to promote novel nanotechnology cancer treatment strategies.

Fast dose fractionation using ultra-short laser accelerated proton pulses can increase cancer cell mortality, which relies on functional PARP1 protein

Radiotherapy is a cornerstone of cancer management. The improvement of spatial dose distribution in the tumor volume by minimizing the dose deposited in the healthy tissues have been a major concern during the last decades. Temporal aspects of dose deposition are yet to be investigated. Laser-plasma-based particle accelerators are able to emit pulsed-proton beams at extremely high peak dose rates (~109 Gy/s) during several nanoseconds. The impact of such dose rates on resistant glioblastoma cell lines, SF763 and U87-MG, was compared to conventionally accelerated protons and X-rays. No difference was observed in DNA double-strand breaks generation and cells killing. The variation of the repetition rate of the proton bunches produced an oscillation of the radio-induced cell susceptibility in human colon carcinoma HCT116 cells, which appeared to be related to the presence of the PARP1 protein and an efficient parylation process. Interestingly, when laser-driven proton bunches were applied at 0.5 Hz, survival of the radioresistant HCT116 p53−/− cells equaled that of its radiosensitive counterpart, HCT116 WT, which was also similar to cells treated with the PARP1 inhibitor Olaparib. Altogether, these results suggest that the application modality of ultrashort bunches of particles could provide a great therapeutic potential in radiotherapy.

Sequential Treatment of Cell Cycle Regulator and Nanoradiosensitizer Achieves Enhanced Radiotherapeutic Outcome.

Nanoradiosensitizers are promising agents for enhancing cancer radiotherapeutic efficiency. Although many attempts have been adopted to improve their radiation enhancement effect through regulation of their size, shape, and/or surface chemistry, few methods have achieved satisfactory radiotherapeutic outcomes. Herein, we propose a sequential drug treatment strategy through cell cycle regulation for achieving improved radiotherapeutic performance of the nanoradiosensitizers. Docetaxel (DTX), a clinically approved first-line drug in breast cancer treatment, is first used to affect the cell cycle distribution and arrest cells in the G2/M phase, which has been proven to be the most effective phase for endocytosis and the most radiosensitive phase for radiotherapy. The cells are then exposed to a commonly used nanoradiosensitizer, gold nanoparticles (GNPs), followed by X-ray irradiation. It is found that by arresting the cancer cells in G2/M phase via the DTX pretreatment, the cellular internalization of GNPs is significantly promoted, therefore enhancing the radiosensitivity of cancer cells. The sensitization enhancement ratioof this sequential DTX/GNP treatment reaches 1.91, which is significantly higher than that (1.29) of GNP treatment. Considering its low cost, simple design, and high feasibility, this sequential drug delivery strategy may hold great potential in radiotherapy.

Abstract 900: Dianhydrogalactitol (VAL-083) has the potential to overcome major challenges in the treatment of DIPG

Abstract Despite decades of clinical trials, children with diffuse intrinsic pontine gliomas (DIPG) continue to have a very poor prognosis and dismal survival. DIPG is inoperable and standard treatment is radiation alone. Major obstacles to the successful treatment of DIPG include 1) an intact blood brain barrier impeding drug penetration, 2) inherent tumor cell resistance mechanisms to conventional chemotherapeutics, and 3) a lack of drug-induced potentiation of radiotherapy. VAL-083 is a structurally unique bi-functional DNA targeting agent that has the potential to overcome these barriers. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue where it rapidly forms interstrand DNA crosslinks at guanine-N7, leading to persistent DNA double strand breaks, cell cycle arrest, and cancer cell death. VAL-083 has cytotoxic activity in several pediatric brain tumors as assessed in NCI-sponsored clinical trials, both as a single agent and in combination with other chemotherapeutics. We recently completed a Phase I/II clinical trial in refractory GBM and established a well-tolerated dosing regimen of VAL-083 in adult brain tumor patients. We have previously demonstrated that VAL-083 cytotoxicity is independent of both the primary, DNA repair protein O6-methylguanine DNA methyltransferase (MGMT), and the secondary, DNA mismatch repair (MMR) system, mechanisms of resistance to temozolomide (TMZ) in vitro. TMZ is commonly used in combination with radiation for the treatment of adult brain tumors but has failed to improve the effect of radiation in DIPG. Importantly, VAL-083 potentiates the effect of radiation and overcomes TMZ resistance in TMZ-resistant adult glioblastoma cancer stem cells (CSCs) and non-CSCs at concentrations that are physiologically achievable in the CNS. Additionally, VAL-083 demonstrated synergistic efficacy in prostate and lung cancer cells with topoisomerase (Topo) inhibitors camptothecin and etoposide, commonly used in the treatment of pediatric brain tumors. In conclusion, VAL-083 is able to 1) cross the blood brain barrier, 2) overcome resistance mechanisms to chemotherapeutics commonly used in the treatment of adult gliomas, and 3) potentiate the effects of radiation in adult glioma cells at physiologically achievable concentrations. Thus, VAL-083 may have the potential to overcome major challenges in DIPG treatment as a single agent, in combination with radiotherapy, or as part of a combination regimen with Topo inhibitors. In the present study, we investigated the effects of VAL-083 in combination with radiation, irinotecan (Topo 1 inhibitor), or Wee1 inhibitor AZD1775 in a panel of DIPG cell lines with varying genetic profiles. The results will provide guidance for the design of animal models studying VAL-083 treatment of DIPG, either as part of a chemo-radiation regimen or in combination with Topo or Wee1 inhibitors. Citation Format: Anne Steino, Beibei Zhai, Jeffrey A. Bacha, Dennis M. Brown, Mads Daugaard, Sabine Mueller. Dianhydrogalactitol (VAL-083) has the potential to overcome major challenges in the treatment of DIPG [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 900.

Abstract PL1: Potential of Radiation Therapy to Convert the Tumor Into an In Situ Vaccine

Abstract Radiotherapy (RT) has revealed an ideal adjuvant to cancer immunotherapy, because of it's ability to convert the irradiated tumor into an individualized, in situ vaccine. 1 DNA damage response (DDR) contributes to immune rejection of tumors, a mechanism at least in part responsible of the success of platinum and RT combinations. 2 RT-induced cell death can evoke T cell memory, inducing effects outside the irradiated field, defined as abscopal. In the setting of metastatic cancer, however, the occurrence of abscopal effects is extremely rare, 3 because of the established immune-suppressive microenvironment. 4 Thus, the pro-immunogenic effects of radiotherapy is best exploited in combination with immunotherapy, 5,6 and combination of RT and immune checkpoint blockade (ICB) has matured to reach clinical translation. 7 8 The issue of RT dose and fractionation is particularly relevant to abscopal responses. 8,9 A mechanism underlying this dose-dependence was recently elucidated. 10 In mice bearing bilateral TSA murine breast carcinoma a single dose of 20 or 30Gy combined with ICB achieved comparable in field control to that of a regimen of 8GyX3 fractions, but only the fractionated regimen induced abscopal responses. An interferon type I (IFN-I) gene signature was associated with the 8GyX3 fractions but not with a single dose of 20 or 30 Gy. IFN-I plays a key role in cross priming and rejection of cancer. 11 RT-generates double strands (ds) DNA fragments reach the cytoplasm of irradiated cells where they are “sensed” by cGAS/STING (cGAS=cyclic GMP-AMP synthase and its adaptor protein STING= stimulator of interferon genes, aka transmembrane protein 173 – TMEM173). cGAS binds cytosolic dsDNA to initiate IFN-I responses upon STING stimulation, resulting in dendritic cell recruitment and cross-priming of effector T-cells, key steps to convert the tumor into an in situ vaccine. In multiple carcinoma murine and human carcinoma cells as the radiation dose increased, cytosolic dsDNA was found to accumulate to a threshold above which induction of three prime repair exonuclease 1 (Trex1) occured, an enzyme that degrades cytoplasmic DNA. Single doses in excess of 10-12 Gy induced Trex1, with rapid degradation of cytosolic dsDNA, and abrogation of IFN induction, impairing RT-induced abscopal effects. These findings support the choice of 3-5 doses of 8 Gy each, when radiotherapy is combined with immunotherapy. Interestingly, a recent dose escalation clinical trial demonstrated an inferior incidence of pathological response (pCR) when breast cancers were irradiated beyond a certain threshold: pCR was 67% in the cohort treated with 8.5 Gy X3 and decreased to 43 and 33% after three fractions of 9.5Gy and 10.5 Gy, respectively. 12 Ongoing investigations are defining optimal sequencing and treatment fields. 1. OncoImmunology 2014; 3: e28518. 2. Oncoimmunology 2017; 6(3): e1274479. 3. Curr Probl Cancer 2016; 40: 25-37. 4. Annu Rev Immunol 2011; 29: 235-71. 5. Int J Radiat Oncol Biol Phys 2004; 58: 862-70. 6. Lancet Oncol 2015; 16(7): 795-803. 7. Clin Cancer Res 2005; 11: 728-34. 8. J Immunother Cancer 2016; 4: 51. 9. Clin Cancer Res 2009; 15(17): 5379-88. 10. Nat Commun 2017; 8: 15618. 11.Trends Immunol 2013; 34(2): 67-73. 12. Int J Radiat Oncol Biol Phys 2013; 85(5): 1193-9. Citation Format: Formenti SC. Potential of Radiation Therapy to Convert the Tumor Into an In Situ Vaccine [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PL1.

First approach to ionizing radiation based 3D printing: fabrication of free standing dose gels using high energy gamma photons

3D printing technique is used for the fabrication of differently shaped objects for industrial, research, medical and societal applications. The technique explores scanning laser beam which interacts with a printing material according to the printing algorithm thus fabricating the required 3D object. In medical field 3D printing is successfully used for fabrication of anatomic bone structures, the first attempts are made to print out artificial skin however there are some limits due to the non-equivalency of printing materials to soft tissue. 3D printing concept might have a big potential in radiotherapy for fabrication of tumor imitators – phantoms for quality control of individual patient treatment.Well known radiation induced polymerization of near tissue equivalent dose gels that are used for dose assessment in radiotherapy is a key issue for the development of the ionizing radiation based 3D printing. However it is to point out, that according to irradiation scenario differently shaped polymerized gel parts usually are being produced inside the gel matrix and cannot be removed from the gel.The aim of this work was to develop high energy photon irradiation based 3D printing method for fabrication of nearly tissue equivalent free-standing 3D dose gel shapes. The first approach for method’s application was fabrication of tumor imitators for brachytherapy treatment.Free standing dose gel shapes that are produced using radiotherapy equipment might serve as medical phantoms (tumour imitators) having the size and shape of a real irradiated volume with dose distribution assessment option within this volume. Concept of this method was firstly proposed in our previous publication (Adlienė et al., 2015).Special dose gels were used as “3D printing material” for the processing of free standing dose gel shapes. Varying dose gel content and adjusting high energy photon irradiation parameters with a pre-planned cancer patient treatment procedure, 3D polymerized gel shapes as the separate free-standing objects were fabricated (3D printing). Comparison of the size and shape of produced 3D objects with the irradiation volumes pre-planned by using standard treatment dose planning system of radiotherapy was performed and the obtained results were analyzed and discussed.

Refining Radiation for the Next Century.

![][1] Wilhelm Roentgen's report more than a century ago describing X-ray imaging fostered in the application of ionizing radiation (IR) for cancer therapy. Today, about half of all the patients with cancer are treated with radiotherapy and it remains one of our most effective

Abstract LB-B18: Radiation therapy with presence of nanoparticles at the tumor cell level: optimizing treatment efficacy through nanoparticle design

Abstract Today, more than half of all cancer patients receive radiotherapy as part of their treatment. However, radiotherapy efficacy is often limited by healthy tissues toxicity and needs to be optimized. One relevant solution is to increase the radiation dose deposition from within the tumor cells. The presence of high atomic number (high-Z) elements within the X-ray pathway increases the probability of interaction with ionizing radiation as compared with tissues (composed of low-Z elements). Likewise, mammalian cells can handle materials at the nanoscale. Therefore, materials made of high-Z elements designed at the nanoscale can enhance the deposit of the radiation dose at the cancer cell level. Still, the most relevant design of these nano-objects has been scarcely explored. Here, we hypothesize that the packing of high-Z elements within the nano-object is a key parameter when considering its design. We used gold and probe how its packing at the nanoscale can achieve the best probability of interaction with ionizing radiation. 50 nm and 2 nm diameter gold nanoparticles coated with 1 nm citrate groups and the gold complex Auranofin (2,3,4,6-tetra-O-acetyl-1-thio-b-D-glucopyranosato-S-[triethyl-phosphine] gold) were considered as representative nano-objects. Many copies of each nano-object were randomly distributed within an artificial cluster to take up 10% of its volume and placed within a cell, reflecting general observation of nanoparticles bioavailability at the subcellular level. Using Monte Carlo simulation, we calculated the energy dose deposition from each cluster when activated by 6 MV energy X-ray source at a depth of 3 cm into the patient. The ratio of energy dose deposition between 50 nm and 2 nm gold nanoparticles and between 50 nm gold nanoparticles and Auranofin was approximately 8 and 70 respectively, regardless of the location of the cluster within the cell. In each case, this reflects the reduced fraction of gold atoms in the nano-object. Indeed, when compared to the 50 nm gold nanoparticle, the 2 nm gold nanoparticle is surrounded by fractionally more citrate, the atoms of which act as passive ‘spectators’ (low-Z atoms). For Auranofin, each gold atom is complexed by organic ligands (low-Z atoms), again acting as passive ‘spectators’. The reduced number of gold atoms per cluster for the 2 nm gold nanoparticles and the gold complexes respectively results in a lower average electron density per cluster. Therefore, for a given cluster filling fraction, the electron density per cluster is the highest for the 50 nm gold nanoparticles. Nanosized objects made of high-Z elements may unlock the potential of radiation therapy by rendering the introduction of a greater energy dose, exactly within the tumor structure without passing through surrounding tissues. Here, taking a realistic approach, we show 50 nm gold nanoparticles achieve better radiation dose deposition than 2 nm gold nanoparticles and gold complexes respectively. Hence, the packing of high-Z element at the nanoscale emerges as a key parameter to achieve effective nanoparticle design and optimize the benefit / risk ratio of radiation therapy. Citation Format: Agnès Pottier, Elsa Borghi, Balder Villagomez-Bernabe, Fred Currell. Radiation therapy with presence of nanoparticles at the tumor cell level: optimizing treatment efficacy through nanoparticle design [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B18.

SP-0192: Potential of radiation therapy to convert the tumor into an in situ vaccine

SP-0192: Potential of radiation therapy to convert the tumor into an in situ vaccine

Oligometastatic disease in prostate cancer, a continuously changing paradigm: patient selection and treatment strategy

The recent publication of the results of a relatively large cohort of patients treated with stereotactic body radiation therapy (SBRT) at the Mayo Clinic for oligometastatic prostate cancer (1) has to be considered as another significant step toward the assessment of the potential of radiation therapy in the optimal management of these “niche” patients.

TU-FG-BRC-01: Cancer and the Immune System: The Basics!

There is substantial current interest in the potential of radiation therapy for synergizing with novel immunotherapies to transform irradiated tumor into an immunogenic hub with capacity to ignite a powerful and adaptive longterm anti-cancer response. Interest stems from new insights into fundamental mechanisms underlying interactions between cancer, radiation and the immune system. Radically new immunotherapy approaches have been proposed, which target the immune system, rather than the cancer itself. Promising preliminary results on subsets of patients have led to a surge in research and clinical trials investigating the potential for combining new immunomodulatory agents with radiation therapy. In this symposia, we undertake a basic review of key topics and questions relating to the potential for combining radiation therapy and new immunotherapy approaches, including a focus on opportunities for medical physicists. Learning Objectives: 1.Gain insight into approaches to combining immunotherapy and radiation therapy. 2.Review latest clinical trial data investigating radiation and immunotherapy. 3.Consider how radiation therapy can better stimulate immunogenicity. 4.Explore opportunities for medical physicists in radiation and immunotherapy M Oldham has funding support from Immunolioght Llc

TU-FG-BRC-04: Opportunities for Medical Physics Contributions to Radiation Immunotherapy

There is substantial current interest in the potential of radiation therapy for synergizing with novel immunotherapies to transform irradiated tumor into an immunogenic hub with capacity to ignite a powerful and adaptive longterm anti-cancer response. Interest stems from new insights into fundamental mechanisms underlying interactions between cancer, radiation and the immune system. Radically new immunotherapy approaches have been proposed, which target the immune system, rather than the cancer itself. Promising preliminary results on subsets of patients have led to a surge in research and clinical trials investigating the potential for combining new immunomodulatory agents with radiation therapy. In this symposia, we undertake a basic review of key topics and questions relating to the potential for combining radiation therapy and new immunotherapy approaches, including a focus on opportunities for medical physicists. Learning Objectives: 1. Gain insight into approaches to combining immunotherapy and radiation therapy. 2. Review latest clinical trial data investigating radiation and immunotherapy. 3. Consider how radiation therapy can better stimulate immunogenicity. 4. Explore opportunities for medical physicists in radiation and immunotherapy M Oldham has funding support from Immunolioght Llc

TU-FG-BRC-00: Radiation and Immunotherapy: How to Ignite Long Term Anti-Cancer Response

There is substantial current interest in the potential of radiation therapy for synergizing with novel immunotherapies to transform irradiated tumor into an immunogenic hub with capacity to ignite a powerful and adaptive longterm anti-cancer response. Interest stems from new insights into fundamental mechanisms underlying interactions between cancer, radiation and the immune system. Radically new immunotherapy approaches have been proposed, which target the immune system, rather than the cancer itself. Promising preliminary results on subsets of patients have led to a surge in research and clinical trials investigating the potential for combining new immunomodulatory agents with radiation therapy. In this symposia, we undertake a basic review of key topics and questions relating to the potential for combining radiation therapy and new immunotherapy approaches, including a focus on opportunities for medical physicists. Learning Objectives: 1. Gain insight into approaches to combining immunotherapy and radiation therapy. 2. Review latest clinical trial data investigating radiation and immunotherapy. 3. Consider how radiation therapy can better stimulate immunogenicity. 4. Explore opportunities for medical physicists in radiation and immunotherapy M Oldham has funding support from Immunolioght Llc