Particle radiotherapy and molecular therapies: mechanisms and strategies towards clinical applications

Abstract Immunotherapy and targeted therapy are now commonly used in clinical trials in combination with radiotherapy for several cancers. While results are promising and encouraging, the molecular mechanisms of the interaction between the drugs and radiation remain largely unknown. This is especially important when switching from conventional photon therapy to particle therapy using protons or heavier ions. Different dose deposition patterns and molecular radiobiology can in fact modify the interaction with drugs and their effectiveness. We will show here that whilst the main molecular players are the same after low and high linear energy transfer radiation exposure, significant differences are observed in post-exposure signalling pathways that may lead to different effects of the drugs. We will also emphasise that the problem of the timing between drug administration and radiation and the fractionation regime are critical issues that need to be addressed urgently to achieve optimal results in combined treatments with particle therapy.

[1]  R. Kanaar,et al.  DNA Double Strand Break Repair Pathways in Response to Different Types of Ionizing Radiation , 2021, Frontiers in Genetics.

[2]  M. Durante,et al.  Physics and biomedical challenges of cancer therapy with accelerated heavy ions , 2021, Nature Reviews Physics.

[3]  John O. Prior,et al.  Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy , 2021, Cancer discovery.

[4]  J. Welsh,et al.  Pulsed Radiation Therapy to Improve Systemic Control of Metastatic Cancer , 2021, Frontiers in Oncology.

[5]  C. Lord,et al.  Targeting the DNA damage response in immuno-oncology: developments and opportunities , 2021, Nature Reviews Cancer.

[6]  S. Ganesan,et al.  Understanding and overcoming resistance to PARP inhibitors in cancer therapy , 2021, Nature Reviews Clinical Oncology.

[7]  P. Zhou,et al.  DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy , 2021, Signal Transduction and Targeted Therapy.

[8]  K. O'Byrne,et al.  Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review , 2021, Frontiers in Molecular Biosciences.

[9]  J. Parsons,et al.  USP9X Is Required to Maintain Cell Survival in Response to High-LET Radiation , 2021, Frontiers in Oncology.

[10]  R. Timmerman,et al.  Future Directions in the Use of SAbR for the Treatment of Oligometastatic Cancers. , 2021, Seminars in radiation oncology.

[11]  Maxim N. Artyomov,et al.  Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads , 2021, Proceedings of the National Academy of Sciences.

[12]  L. Zhong,et al.  Small molecules in targeted cancer therapy: advances, challenges, and future perspectives , 2021, Signal Transduction and Targeted Therapy.

[13]  R. Johnstone,et al.  Regulatory T cells shape the differential impact of radiation dose-fractionation schedules on host innate and adaptive anti-tumor immune defenses: Immunosuppressive implications of radiotherapy. , 2021, International journal of radiation oncology, biology, physics.

[14]  Tiara Bunga Mayang Permata,et al.  Modulation of immune responses by DNA damage signaling. , 2021, DNA repair.

[15]  S. Jackson,et al.  Interfaces between cellular responses to DNA damage and cancer immunotherapy , 2021, Genes & development.

[16]  L. Bouwens,et al.  Fractionated radiation severely reduces the number of CD8+ T cells and mature antigen presenting cells within lung tumors. , 2021, International journal of radiation oncology, biology, physics.

[17]  A. Murphy,et al.  Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses , 2021, Science Immunology.

[18]  Laurentiu M. Pop,et al.  Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy (PULSAR) in preclinical models enhances single agent immune checkpoint blockade. , 2021, International journal of radiation oncology, biology, physics.

[19]  J. Pinto,et al.  Biological bases of cancer immunotherapy , 2021, Expert Reviews in Molecular Medicine.

[20]  F. Brandalise,et al.  A New Platinum-Based Prodrug Candidate for Chemotherapy and Its Synergistic Effect With Hadrontherapy: Novel Strategy to Treat Glioblastoma , 2021, Frontiers in Neuroscience.

[21]  M. Durante,et al.  Modeling Radioimmune Response—Current Status and Perspectives , 2021, Frontiers in Oncology.

[22]  H. Park,et al.  Downregulation of Mcl-1 by Panobinostat Potentiates Proton Beam Therapy in Hepatocellular Carcinoma Cells , 2021, Cells.

[23]  R. Weichselbaum,et al.  Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity , 2021, Science Translational Medicine.

[24]  J. Sarkaria,et al.  Inhibition of ATM Induces Hypersensitivity to Proton Irradiation by Upregulating Toxic End Joining , 2021, Cancer Research.

[25]  L. Galluzzi,et al.  Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER+ Breast Cancer , 2021, Clinical Cancer Research.

[26]  A. Chinnaiyan,et al.  Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination , 2021, Nature Medicine.

[27]  H. Pyo,et al.  Proton beam therapy reduces the risk of severe radiation-induced lymphopenia during chemoradiotherapy for locally advanced non-small cell lung cancer: A comparative analysis of proton versus photon therapy. , 2020, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[28]  Yi-long Wu,et al.  Brief report: Four-year survival with durvalumab after chemoradiotherapy in Stage III NSCLC - an update from the PACIFIC trial. , 2020, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[29]  J. Parsons,et al.  The E3 Ubiquitin Ligase NEDD4L Targets OGG1 for Ubiquitylation and Modulates the Cellular DNA Damage Response , 2020, Frontiers in Cell and Developmental Biology.

[30]  Haidong Dong,et al.  Radiation and immunotherapy: emerging mechanisms of synergy , 2020, Journal of thoracic disease.

[31]  Joe Y. Chang,et al.  Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. , 2020, The Lancet. Respiratory medicine.

[32]  J. Welsh,et al.  Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma , 2020, Journal for ImmunoTherapy of Cancer.

[33]  M. Durante,et al.  Carbon Ion Radiobiology , 2020, Cancers.

[34]  M. Durante,et al.  Reduction of lung metastases in a mouse osteosarcoma model treated with carbon ions and immune checkpoint inhibitors. , 2020, International journal of radiation oncology, biology, physics.

[35]  W. V. van Cappellen,et al.  Comparison of High- and Low-LET Radiation-Induced DNA Double-Strand Break Processing in Living Cells , 2020, International journal of molecular sciences.

[36]  N. Agarwal,et al.  Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors. , 2020, European urology.

[37]  R. Mohan,et al.  Proton Therapy Reduces the Likelihood of High-Grade Radiation-Induced Lymphopenia in Glioblastoma Patients: Phase II Randomized Study of Protons vs. Photons. , 2020, Neuro-oncology.

[38]  J. Parsons,et al.  Base excision repair and its implications to cancer therapy , 2020, Essays in biochemistry.

[39]  Caicun Zhou,et al.  cGAS-STING, an important pathway in cancer immunotherapy , 2020, Journal of Hematology & Oncology.

[40]  J. Welsh,et al.  Interaction between lymphopenia, radiotherapy technique, dosimetry, and survival outcomes in lung cancer patients receiving combined immunotherapy and radiotherapy. , 2020, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[41]  M. Weller,et al.  Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma , 2020, JAMA oncology.

[42]  V. Hornung,et al.  Molecular mechanisms and cellular functions of cGAS–STING signalling , 2020, Nature Reviews Molecular Cell Biology.

[43]  L. Galluzzi,et al.  Immunomodulation by anticancer cell cycle inhibitors , 2020, Nature Reviews Immunology.

[44]  P. Lambin,et al.  Lymphocyte-Sparing Radiotherapy: The Rationale for Protecting Lymphocyte-rich Organs When Combining Radiotherapy With Immunotherapy. , 2020, Seminars in radiation oncology.

[45]  F. Marincola,et al.  Consensus guidelines for the definition, detection and interpretation of immunogenic cell death , 2020, Journal for ImmunoTherapy of Cancer.

[46]  M. Pruschy,et al.  The relative biological effectiveness of proton irradiation in dependence of DNA damage repair. , 2020, The British journal of radiology.

[47]  G. Iliakis,et al.  Chromosome breaks generated by low doses of ionizing radiation in G2-phase are processed exclusively by gene conversion. , 2020, DNA repair.

[48]  Bjorn Baselet,et al.  Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance , 2020, Frontiers in Oncology.

[49]  M. Durante,et al.  Differential Repair Protein Recruitment at Sites of Clustered and Isolated DNA Double-Strand Breaks Produced by High-Energy Heavy Ions , 2020, Scientific Reports.

[50]  M. Cornforth Occam’s broom and the dirty DSB: cytogenetic perspectives on cellular response to changes in track structure and ionization density , 2020, International journal of radiation biology.

[51]  A. Balmain,et al.  Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice , 2020, Nature Communications.

[52]  A. Shibata,et al.  Canonical DNA non-homologous end-joining; capacity versus fidelity , 2020, The British journal of radiology.

[53]  N. Sharma,et al.  Clustered DNA Double-Strand Breaks: Biological Effects and Relevance to Cancer Radiotherapy , 2020, Genes.

[54]  J. Metz,et al.  Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer. , 2019, JAMA oncology.

[55]  G. Iliakis,et al.  Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer , 2019, Cancers.

[56]  Jingfang Zhao,et al.  Comparison of the effects of photon, proton and carbon-ion radiation on the ecto-calreticulin exposure in various tumor cell lines. , 2019, Annals of translational medicine.

[57]  D. Aoki,et al.  Significance of PD-L1 expression in carbon-ion radiotherapy for uterine cervical adeno/adenosquamous carcinoma , 2019, Journal of gynecologic oncology.

[58]  J. Aten,et al.  Ultra-soft X-ray system for imaging the early cellular responses to X-ray induced DNA damage , 2019, Nucleic acids research.

[59]  O. Elemento,et al.  Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system , 2019, Genome Medicine.

[60]  Nicole M. Chapman,et al.  Upregulation of PD-L1 via HMGB1-Activated IRF3 and NF-κB Contributes to UV Radiation-Induced Immune Suppression. , 2019, Cancer research.

[61]  R. Sánchez-Prieto,et al.  P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: Implication in cancer therapy. , 2019, Cancer letters.

[62]  Clemens Grassberger,et al.  Assessing the interactions between radiotherapy and antitumour immunity , 2019, Nature Reviews Clinical Oncology.

[63]  C. Trautmann,et al.  Applied nuclear physics at the new high-energy particle accelerator facilities , 2019, Physics Reports.

[64]  A. Shibata,et al.  Novel Approaches to Improve the Efficacy of Immuno-Radiotherapy , 2019, Front. Oncol..

[65]  M. Koizumi,et al.  Carbon ion irradiation enhances the antitumor efficacy of dual immune checkpoint blockade therapy both for local and distant sites in murine osteosarcoma , 2019, Oncotarget.

[66]  M. Kneilling,et al.  Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy. , 2018, JCI insight.

[67]  M. Hausmann,et al.  Recruitment of 53BP1 Proteins for DNA Repair and Persistence of Repair Clusters Differ for Cell Types as Detected by Single Molecule Localization Microscopy , 2018, International journal of molecular sciences.

[68]  Joe Y. Chang,et al.  Time to abandon single-site irradiation for inducing abscopal effects , 2018, Nature Reviews Clinical Oncology.

[69]  Yuzhen Niu,et al.  Genistein sensitizes glioblastoma cells to carbon ions via inhibiting DNA-PKcs phosphorylation and subsequently repressing NHEJ and delaying HR repair pathways. , 2018, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[70]  R. Emerson,et al.  Radiotherapy induces responses of lung cancer to CTLA-4 blockade , 2018, Nature Medicine.

[71]  Yoshiyuki Suzuki,et al.  High linear energy transfer carbon-ion irradiation increases the release of the immune mediator high mobility group box 1 from human cancer cells , 2018, Journal of radiation research.

[72]  C. Drake,et al.  Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy , 2018, Clinical Cancer Research.

[73]  M. Durante,et al.  Radiation-Induced Chromosomal Aberrations and Immunotherapy: Micronuclei, Cytosolic DNA, and Interferon-Production Pathway , 2018, Front. Oncol..

[74]  Arnaud Boyer,et al.  Durvalumab after chemoradiotherapy in stage III non-small cell lung cancer. , 2018, Journal of thoracic disease.

[75]  Alan E. Tomkinson,et al.  Repair of DNA double-strand breaks by mammalian alternative end-joining pathways , 2018, The Journal of Biological Chemistry.

[76]  R. Mohan,et al.  Radiation-Associated Lymphopenia and Outcomes of Patients with Unresectable Hepatocellular Carcinoma Treated with Radiotherapy , 2018, Journal of hepatocellular carcinoma.

[77]  J. Hesser,et al.  Using immunotherapy to boost the abscopal effect , 2018, Nature Reviews Cancer.

[78]  Steven H. Lin,et al.  A systematic review of the influence of radiation-induced lymphopenia on survival outcomes in solid tumors. , 2018, Critical reviews in oncology/hematology.

[79]  M. Durante,et al.  Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer , 2018, Physics in medicine and biology.

[80]  Samuel F. Bakhoum,et al.  Chromosomal instability drives metastasis through a cytosolic DNA response , 2017, Nature.

[81]  A. Shibata,et al.  3D-structured illumination microscopy reveals clustered DNA double-strand break formation in widespread γH2AX foci after high LET heavy-ion particle radiation , 2017, Oncotarget.

[82]  Tiara Bunga Mayang Permata,et al.  DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells , 2017, Nature Communications.

[83]  J. Parsons,et al.  Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response , 2017, International journal of radiation oncology, biology, physics.

[84]  S. Formenti Optimizing Dose Per Fraction: A New Chapter in the Story of the Abscopal Effect? , 2017, International journal of radiation oncology, biology, physics.

[85]  M. Christmann,et al.  Epigenetic regulation of DNA repair genes and implications for tumor therapy. , 2017, Mutation research.

[86]  D. Gomez,et al.  Lymphocyte Nadir and Esophageal Cancer Survival Outcomes After Chemoradiation Therapy. , 2017, International journal of radiation oncology, biology, physics.

[87]  S. Demaria,et al.  TREX1 dictates the immune fate of irradiated cancer cells , 2017, Oncoimmunology.

[88]  Dennis E Discher,et al.  Mitotic progression following DNA damage enables pattern recognition within micronuclei , 2017, Nature.

[89]  M. Durante,et al.  Generating and grading the abscopal effect: proposal for comprehensive evaluation of combination immunoradiotherapy in mouse models , 2017 .

[90]  C. N. Coleman,et al.  DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity , 2017, Nature Communications.

[91]  Jan Theys,et al.  Combining radiotherapy with immunotherapy: the past, the present and the future , 2017, The British journal of radiology.

[92]  Marco Durante,et al.  Charged-particle therapy in cancer: clinical uses and future perspectives , 2017, Nature Reviews Clinical Oncology.

[93]  T. Nakano,et al.  Intravenous dendritic cell administration enhances suppression of lung metastasis induced by carbon-ion irradiation , 2017, Journal of radiation research.

[94]  I. Koturbash,et al.  Effects of ionizing radiation on DNA methylation: from experimental biology to clinical applications , 2017, International journal of radiation biology.

[95]  U. Kutay,et al.  Mechanisms and functions of nuclear envelope remodelling , 2017, Nature Reviews Molecular Cell Biology.

[96]  M. Durante,et al.  Does Heavy Ion Therapy Work Through the Immune System? , 2016, International journal of radiation oncology, biology, physics.

[97]  M. Prados,et al.  Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth. , 2016, Neuro-oncology.

[98]  Zhijian J. Chen,et al.  Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing , 2016, Nature Immunology.

[99]  T. Illidge,et al.  Stereotactic ablative radiotherapy and immunotherapy combinations: turning the future into systemic therapy? , 2016, The British journal of radiology.

[100]  T. Shimokawa,et al.  The Future of Combining Carbon-Ion Radiotherapy with Immunotherapy: Evidence and Progress in Mouse Models. , 2016, International journal of particle therapy.

[101]  A. Sartori,et al.  Controlling DNA-End Resection: An Emerging Task for Ubiquitin and SUMO , 2016, Front. Genet..

[102]  Marco Durante,et al.  Nuclear physics in particle therapy: a review , 2016, Reports on progress in physics. Physical Society.

[103]  J. Debus,et al.  Next generation multi-scale biophysical characterization of high precision cancer particle radiotherapy using clinical proton, helium-, carbon- and oxygen ion beams , 2016, Oncotarget.

[104]  J. Rodgers,et al.  Short DNA Fragments Are a Hallmark of Heavy Charged-Particle Irradiation and May Underlie Their Greater Therapeutic Efficacy , 2016, Front. Oncol..

[105]  M. Bernstein,et al.  Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell-Mediated Killing. , 2016, International journal of radiation oncology, biology, physics.

[106]  Mechthild Krause,et al.  Radiation oncology in the era of precision medicine , 2016, Nature Reviews Cancer.

[107]  A. Shibata,et al.  Visualization of complex DNA double-strand breaks in a tumor treated with carbon ion radiotherapy , 2016, Scientific Reports.

[108]  M. Durante,et al.  Efficient Rejoining of DNA Double-Strand Breaks despite Increased Cell-Killing Effectiveness following Spread-Out Bragg Peak Carbon-Ion Irradiation , 2016, Front. Oncol..

[109]  S. Kampfer,et al.  Paving the Road for Modern Particle Therapy – What Can We Learn from the Experience Gained with Fast Neutron Therapy in Munich? , 2015, Front. Oncol..

[110]  T. Nakano,et al.  Combining carbon ion irradiation and non-homologous end-joining repair inhibitor NU7026 efficiently kills cancer cells , 2015, Radiation oncology.

[111]  T. Nakano,et al.  Combining carbon ion irradiation and non-homologous end-joining repair inhibitor NU7026 efficiently kills cancer cells , 2015, Radiation Oncology.

[112]  G. Iliakis,et al.  Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations. , 2015, Mutation research. Genetic toxicology and environmental mutagenesis.

[113]  Matylda Sczaniecka-Clift,et al.  Systematic E2 screening reveals a UBE2D–RNF138–CtIP axis promoting DNA repair , 2015, Nature Cell Biology.

[114]  Matthias Guckenberger,et al.  Differential DNA repair pathway choice in cancer cells after proton- and photon-irradiation. , 2015, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[115]  S. Penfold,et al.  Development of a radiation track structure clustering algorithm for the prediction of DNA DSB yields and radiation induced cell death in Eukaryotic cells , 2015, Physics in medicine and biology.

[116]  Martin L. Miller,et al.  Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer , 2015, Science.

[117]  Yoshiyuki Suzuki,et al.  Carbon-ion beams induce production of an immune mediator protein, high mobility group box 1, at levels comparable with X-ray irradiation , 2015, Journal of radiation research.

[118]  Takeji Sakae,et al.  The Major DNA Repair Pathway after Both Proton and Carbon-Ion Radiation is NHEJ, but the HR Pathway is More Relevant in Carbon Ions , 2015, Radiation research.

[119]  R. Pötter,et al.  Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. , 2015, The Lancet. Oncology.

[120]  M. Durante,et al.  DNA end resection is needed for the repair of complex lesions in G1-phase human cells , 2014, Cell cycle.

[121]  T. Nakano,et al.  Nonhomologous End-Joining Repair Plays a More Important Role than Homologous Recombination Repair in Defining Radiosensitivity after Exposure to High-LET Radiation , 2014, Radiation research.

[122]  S. Demaria,et al.  Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death , 2014, Oncoimmunology.

[123]  G. Kornek,et al.  Targeted drugs in combination with radiotherapy for the treatment of solid tumors: current state and future developments , 2013, Expert review of clinical pharmacology.

[124]  P. Jeggo,et al.  The complexity of DNA double strand breaks is a critical factor enhancing end-resection. , 2013, DNA repair.

[125]  M Durante,et al.  Including oxygen enhancement ratio in ion beam treatment planning: model implementation and experimental verification , 2013, Physics in medicine and biology.

[126]  S. Demaria,et al.  Radiation as an immunological adjuvant: current evidence on dose and fractionation , 2012, Front. Oncol..

[127]  K. Iwamoto,et al.  Maximizing tumor immunity with fractionated radiation. , 2012, International journal of radiation oncology, biology, physics.

[128]  P. Jeggo,et al.  The role of homologous recombination in radiation-induced double-strand break repair. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[129]  David J. Chen,et al.  Unrepaired clustered DNA lesions induce chromosome breakage in human cells , 2011, Proceedings of the National Academy of Sciences.

[130]  M. Durante,et al.  Protein acetylation within the cellular response to radiation , 2011, Journal of cellular physiology.

[131]  J. Baulch,et al.  The Effect of Radiation Quality on Genomic DNA Methylation Profiles in Irradiated Human Cell Lines , 2011, Radiation research.

[132]  J. Baulch,et al.  Radiation-induced epigenetic alterations after low and high LET irradiations. , 2011, Mutation research.

[133]  Jayanta Chaudhuri,et al.  CtIP promotes microhomology-mediated alternative end-joining during class switch recombination , 2010, Nature Structural &Molecular Biology.

[134]  T. Nakano,et al.  Combining carbon ion radiotherapy and local injection of α-galactosylceramide-pulsed dendritic cells inhibits lung metastases in an in vivo murine model. , 2010, International journal of radiation oncology, biology, physics.

[135]  M. Durante,et al.  Heavy-ion induced chromosomal aberrations: a review. , 2010, Mutation research.

[136]  Y. Yonemitsu,et al.  Carbon‐ion beam treatment induces systemic antitumor immunity against murine squamous cell carcinoma , 2010, Cancer.

[137]  S W Hell,et al.  Biological dose estimation of UVA laser microirradiation utilizing charged particle-induced protein foci. , 2010, Mutagenesis.

[138]  N. Kawashima,et al.  Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody , 2009, Clinical Cancer Research.

[139]  Irene L. Ibañez,et al.  Induction and rejoining of DNA double strand breaks assessed by H2AX phosphorylation in melanoma cells irradiated with proton and lithium beams. , 2009, International journal of radiation oncology, biology, physics.

[140]  S. Demaria,et al.  Systemic effects of local radiotherapy. , 2009, The Lancet. Oncology.

[141]  M. Beuve,et al.  Different mechanisms of cell death in radiosensitive and radioresistant p53 mutated head and neck squamous cell carcinoma cell lines exposed to carbon ions and x-rays. , 2009, International journal of radiation oncology, biology, physics.

[142]  M. Durante,et al.  Live cell microscopy analysis of radiation-induced DNA double-strand break motion , 2009, Proceedings of the National Academy of Sciences.

[143]  Hans Blattmann,et al.  Tumor therapy with heavy charged particles , 2008 .

[144]  J. Wise,et al.  Mutation research, genetic toxicology and environmental mutagenesis , 2005 .

[145]  J. Kiefer Mutagenic effects of heavy charged particles. , 2002, Journal of radiation research.

[146]  M. Durante,et al.  X-rays vs. carbon-ion tumor therapy: cytogenetic damage in lymphocytes. , 2000, International journal of radiation oncology, biology, physics.

[147]  T. Phillips,et al.  Neon ion radiotherapy: results of the phase I/II clinical trial. , 1991, International journal of radiation oncology, biology, physics.

[148]  M. Durante,et al.  Proton theraPy sPecial feature: review article harnessing radiation to improve immunotherapy: better with particles? , 2020 .

[149]  P. Venkat,et al.  Systematic review of case reports on the abscopal effect. , 2016, Current problems in cancer.

[150]  A. Coray,et al.  Deficiency in homologous recombination renders Mammalian cells more sensitive to proton versus photon irradiation. , 2014, International journal of radiation oncology, biology, physics.

[151]  Y. Miki,et al.  [PARP inhibitors for cancer therapy]. , 2011, Gan to kagaku ryoho. Cancer & chemotherapy.

[152]  Yu Zhang,et al.  An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway , 2011, Nature Structural &Molecular Biology.

[153]  T. Delaney Proton therapy in the clinic. , 2011, Frontiers of radiation therapy and oncology.

[154]  A. Takahashi,et al.  High LET heavy ion radiation induces p53-independent apoptosis. , 2009, Journal of radiation research.

[155]  George D Wilson,et al.  Biologic basis for combining drugs with radiation. , 2006, Seminars in radiation oncology.

[156]  D T Goodhead,et al.  Track structure in radiation biology: theory and applications. , 1998, International journal of radiation biology.