Rationale for combination of radiation therapy and immune checkpoint blockers to improve cancer treatment

References

• Burstein HJ, Krilov L, Aragon-Ching JB, et al. Clinical cancer advances 2017: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2017;35:1341–1367.
   Web of Science ®Google Scholar
• Larsen IK, Møller B, Johannesen TB, et al. Cancer in Norway 2017. Cancer Incidence, Mortality, Survival Preval Norway. 2018;1–103.
   Google Scholar
• Borras JM, Lievens Y, Barton M, et al. How many new cancer patients in Europe will require radiotherapy by 2025? An ESTRO-HERO analysis. Radiother Oncol. 2016;119:5–11.
   PubMed Web of Science ®Google Scholar
• Baumann M, Krause M, Overgaard J, et al. Radiation oncology in the era of precision medicine. Nat Rev Cancer. 2016;16:234–249.
   PubMed Web of Science ®Google Scholar
• Hoyer M, Muren LP, Glimelius B. The evolution of radiotherapy techniques in the management of prostate cancer. Acta Oncol. 2015;54:821–824.
   PubMed Web of Science ®Google Scholar
• Combs SE, Debus J. Treatment with heavy charged particles: systematic review of clinical data and current clinical (comparative) trials. Acta Oncol. 2013;52:1272–1286.
   PubMed Web of Science ®Google Scholar
• Jakobi A, Stutzer K, Bandurska-Luque A, et al. NTCP reduction for advanced head and neck cancer patients using proton therapy for complete or sequential boost treatment versus photon therapy. Acta Oncol. 2015;54:1658–1664.
   PubMed Web of Science ®Google Scholar
• Kamada T, Tsujii H, Blakely EA, et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol. 2015;16:e93–e100.
   PubMed Web of Science ®Google Scholar
• Dahl O, Brydøy M. The pioneers behind immune checkpoint blockers awarded the Nobel Prize in physiology or medicine 2018. Acta Oncologica. 2019;58:
   Web of Science ®Google Scholar
• Puck TT, Morkovin D, Marcus PI, et al. Action of x-rays on mammalian cells. II. Survival curves of cells from normal human tissues. J Exp Med. 1957;106:485–500.
   PubMed Web of Science ®Google Scholar
• Iliakis G, Wang Y, Guan J, et al. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene. 2003;22:5834–5847.
   PubMed Web of Science ®Google Scholar
• Mikkelsen RB, Wardman P. Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms. Oncogene. 2003;22:5734–5754.
   PubMed Web of Science ®Google Scholar
• Ward JF. DNA damage as the cause of ionizing radiation-induced gene activation. Radiat Res. 1994;138:S85–S88.
   PubMed Web of Science ®Google Scholar
• Helleday T, Petermann E, Lundin C, et al. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer. 2008;8:193–204.
   PubMed Web of Science ®Google Scholar
• Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene. 2003;22:5897–5906.
   PubMed Web of Science ®Google Scholar
• Fei P, El-Deiry WS. P53 and radiation responses. Oncogene. 2003;22:5774–5783.
   PubMed Web of Science ®Google Scholar
• Balcer-Kubiczek EK. Apoptosis in radiation therapy: a double-edged sword. Exp Oncol. 2012;34:277–285.
   PubMedGoogle Scholar
• Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–257.
   PubMed Web of Science ®Google Scholar
• Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30:1913–1930.
   PubMed Web of Science ®Google Scholar
• White E, Mehnert JM, Chan CS. Autophagy, metabolism, and cancer. Clin Cancer Res. 2015;21:5037–5046.
   PubMed Web of Science ®Google Scholar
• Firat E, Gaedicke S, Tsurumi C, et al. Delayed cell death associated with mitotic catastrophe in γ-irradiated stem-like glioma cells. Radiat Oncol. 2011;6:71.
   PubMed Web of Science ®Google Scholar
• Mc Gee MM. Targeting the mitotic catastrophe signaling pathway in cancer. Mediators Inflamm. 2015;2015:146282.
   PubMed Web of Science ®Google Scholar
• Vakifahmetoglu H, Olsson M, Zhivotovsky B. Death through a tragedy: mitotic catastrophe. Cell Death Differ. 2008;15:1153–1162.
   PubMed Web of Science ®Google Scholar
• Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–740.
   PubMed Web of Science ®Google Scholar
• Gewirtz DA, Alotaibi M, Yakovlev VA, et al. Tumor cell recovery from senescence induced by radiation with PARP inhibition. Radiat Res. 2016;186:327–332.
   PubMed Web of Science ®Google Scholar
• Wunderlich R, Ruehle PF, Deloch L, et al. Interconnection between DNA damage, senescence, inflammation, and cancer. Front Biosci (Landmark Ed). 2017;22:348–369.
   PubMed Web of Science ®Google Scholar
• Matt S, Hofmann TG. The DNA damage-induced cell death response: a roadmap to kill cancer cells. Cell Mol Life Sci. 2016;73:2829–2850.
   PubMed Web of Science ®Google Scholar
• Rodemann HP, Blaese MA. Responses of normal cells to ionizing radiation. Semin Radiat Oncol. 2007;17:81–88.
   PubMed Web of Science ®Google Scholar
• Roos WP, Thomas AD, Kaina B. DNA damage and the balance between survival and death in cancer biology. Nat Rev Cancer. 2016;16:20–33.
   PubMed Web of Science ®Google Scholar
• Kurtova AV, Xiao J, Mo Q, et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature. 2015;517:209–213.
   PubMed Web of Science ®Google Scholar
• Tannock IF. Cancer: resistance through repopulation. Nature. 2015;517:152–153.
   PubMed Web of Science ®Google Scholar
• Ondrej M, Cechakova L, Durisova K, et al. To live or let die: unclear task of autophagy in the radiosensitization battle. Radiother Oncol. 2016;119:265–275.
   PubMed Web of Science ®Google Scholar
• Kim YH, Yoo KC, Cui YH, et al. Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization. Cancer Lett. 2014;354:132–141.
   PubMed Web of Science ®Google Scholar
• Cordes N, Rodel F, Rodemann HP. Molecular signaling pathways. mechanisms and clinical use. Strahlenther Onkol. 2012;188 Suppl 3:308–311.
   PubMed Web of Science ®Google Scholar
• Kachikwu EL, Iwamoto KS, Liao YP, et al. Radiation enhances regulatory T cell representation. Int J Radiat Oncol Biol Phys. 2011;81:1128–1135.
   PubMed Web of Science ®Google Scholar
• Order SE. The effects of therapeutic irradiation on lymphocytes and immunity. Cancer. 1977;39:737–743.
   PubMed Web of Science ®Google Scholar
• Wara WM, Phillips TL, Wara DW, et al. Immunosuppression following radiation therapy for carcinoma of the nasopharynx. Am J Roentgenol Radium Ther Nucl Med. 1975;123:482–485.
   PubMedGoogle Scholar
• Anscher MS. Targeting the TGF-beta1 pathway to prevent normal tissue injury after cancer therapy. Oncologist. 2010;15:350–359.
   PubMed Web of Science ®Google Scholar
• Derer A, Frey B, Fietkau R, et al. Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. Cancer Immunol Immunother. 2016;65:779–786.
   PubMed Web of Science ®Google Scholar
• Desai S, Kumar A, Laskar S, et al. Cytokine profile of conditioned medium from human tumor cell lines after acute and fractionated doses of gamma radiation and its effect on survival of bystander tumor cells. Cytokine. 2013;61:54–62.
   PubMed Web of Science ®Google Scholar
• Marabelle A, Filatenkov A, Sagiv-Barfi I, et al. Radiotherapy and toll-like receptor agonists. Semin Radiat Oncol. 2015;25:34–39.
   PubMed Web of Science ®Google Scholar
• Roses RE, Xu M, Koski GK, et al. Radiation therapy and toll-like receptor signaling: implications for the treatment of cancer. Oncogene. 2008;27:200–207.
   PubMed Web of Science ®Google Scholar
• Barsoum IB, Smallwood CA, Siemens DR, et al. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014;74:665–674.
   PubMed Web of Science ®Google Scholar
• Jeong H, Bok S, Hong BJ, et al. Radiation-induced immune responses: mechanisms and therapeutic perspectives. Blood Res. 2016;51:157–163.
   PubMed Web of Science ®Google Scholar
• Wennerberg E, Lhuillier C, Vanpouille-Box C, et al. Barriers to radiation-induced in situ tumor vaccination. Front Immunol. 2017;8:229.
   PubMed Web of Science ®Google Scholar
• McBride WH, Chiang CS, Olson JL, et al. A sense of danger from radiation. Radiat Res. 2004;162:1–19.
   PubMed Web of Science ®Google Scholar
• Fuchs EJ, Matzinger P. Is cancer dangerous to the immune system? Semin Immunol. 1996;8:271–280.
   PubMedGoogle Scholar
• Garg AD, Galluzzi L, Apetoh L, et al. Molecular and translational classifications of DAMPs in immunogenic cell death. Front Immunol. 2015;6:588.
   PubMed Web of Science ®Google Scholar
• Pradeu T, Cooper EL. The danger theory: 20 years later. Front Immunol. 2012;3:287.
   PubMed Web of Science ®Google Scholar
• Eisenbacher JL, Schrezenmeier H, Jahrsdorfer B, et al. S100A4 and uric acid promote mesenchymal stromal cell induction of IL-10+/IDO + lymphocytes. J Immunol. 2014;192:6102–6110.
   PubMed Web of Science ®Google Scholar
• Land WG, Agostinis P, Gasser S, et al. Transplantation and damage-associated molecular patterns (DAMPs). Am J Transplant. 2016;16:3338–3361.
   PubMed Web of Science ®Google Scholar
• Sharabi AB, Lim M, DeWeese TL, et al. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015;16:e498–e509.
   PubMed Web of Science ®Google Scholar
• Lotfi R, Kaltenmeier C, Lotze MT, et al. Until death do us part: necrosis and oxidation promote the tumor microenvironment. Transfus Med Hemother. 2016;43:120–132.
   PubMed Web of Science ®Google Scholar
• Ohta A. A metabolic immune checkpoint: adenosine in tumor microenvironment. Front Immunol. 2016;7:e109.
   PubMed Web of Science ®Google Scholar
• Vega VL, Rodriguez-Silva M, Frey T, et al. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol. 2008;180:4299–4307.
   PubMed Web of Science ®Google Scholar
• Li K, Qu S, Chen X, et al. Promising targets for cancer immunotherapy: TLRs, RLRs, and STING-mediated innate immune pathways. Int J Mol Sci. 2017;18:E404.
   Web of Science ®Google Scholar
• Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Comms. 2017;8:15618.
   PubMed Web of Science ®Google Scholar
• Liang H, Deng L, Hou Y, et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun. 2017;8:1736.
   PubMed Web of Science ®Google Scholar
• Filatenkov A, Baker J, Mueller AM, et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin Cancer Res. 2015;21:3727–3739.
   PubMed Web of Science ®Google Scholar
• Golden EB, Frances D, Pellicciotta I, et al. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology. 2014;3:e28518.
   PubMed Web of Science ®Google Scholar
• Lugade AA, Moran JP, Gerber SA, et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 2005;174:7516–7523.
   PubMed Web of Science ®Google Scholar
• Muraro E, Furlan C, Avanzo M, et al. Local high-dose radiotherapy induces systemic immunomodulating effects of potential therapeutic relevance in oligometastatic breast cancer. Front Immunol. 2017;8:1476.
   PubMed Web of Science ®Google Scholar
• DeGiorgi LS. Regression of pulmonary metastases during radiation to a hypernephroma. Immunity and cancer. Cancer. 1972;30:895–899.
   PubMed Web of Science ®Google Scholar
• Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009;10:718–726.
   PubMed Web of Science ®Google Scholar
• Michot JM, Mazeron R, Dercle L, et al. Abscopal effect in a Hodgkin lymphoma patient treated by an anti-programmed death 1 antibody. Eur J Cancer. 2016;66:91–94.
   PubMed Web of Science ®Google Scholar
• Reynders K, Illidge T, Siva S, et al. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev. 2015;41:503–510.
   PubMed Web of Science ®Google Scholar
• Mole RH. Whole body irradiation; radiobiology or medicine? Br J Radiol. 1953;26:234–241.
   PubMed Web of Science ®Google Scholar
• Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105:256–265.
   PubMed Web of Science ®Google Scholar
• Lock M, Muinuddin A, Kocha WI, et al. Abscopal effects: case report and emerging opportunities. Cureus. 2015;7:e344.
   PubMed Web of Science ®Google Scholar
• Rubner Y, Wunderlich R, Ruhle PF, et al. How does ionizing irradiation contribute to the induction of anti-tumor immunity? Front Oncol. 2012;2:75.
   PubMedGoogle Scholar
• Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58:862–870.
   PubMed Web of Science ®Google Scholar
• Chakravarty PK, Alfieri A, Thomas EK, et al. Flt3-ligand administration after radiation therapy prolongs survival in a murine model of metastatic lung cancer. Cancer Res. 1999;59:6028–6032.
   PubMed Web of Science ®Google Scholar
• Grass GD, Krishna N, Kim S. The immune mechanisms of abscopal effect in radiation therapy. Curr Probl Cancer. 2016;40:10–24.
   PubMed Web of Science ®Google Scholar
• Chandra RA, Wilhite TJ, Balboni TA, et al. A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology. 2015;4:e1046028.
   PubMed Web of Science ®Google Scholar
• Grimaldi AM, Simeone E, Giannarelli D, et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology. 2014;3:e28780.
   PubMed Web of Science ®Google Scholar
• Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–931.
   PubMed Web of Science ®Google Scholar
• Chicas-Sett R, Morales-Orue I, Rodriguez-Abreu D, et al. Combining radiotherapy and ipilimumab induces clinically relevant radiation-induced abscopal effects in metastatic melanoma patients: a systematic review. Clin Transl Radiat Oncol. 2018;9:5–11.
   PubMed Web of Science ®Google Scholar
• Siva S, MacManus MP, Martin RF, et al. Abscopal effects of radiation therapy: a clinical review for the radiobiologist. Cancer Lett. 2015;356:82–90.
   PubMed Web of Science ®Google Scholar
• Levy A, Chargari C, Marabelle A, et al. Can immunostimulatory agents enhance the abscopal effect of radiotherapy? Eur J Cancer. 2016;62:36–45.
   PubMed Web of Science ®Google Scholar
• Ngwa W, Irabor OC, Schoenfeld JD, et al. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer. 2018;18:313–322.
   PubMed Web of Science ®Google Scholar
• Ishihara D, Pop L, Takeshima T, et al. Rationale and evidence to combine radiation therapy and immunotherapy for cancer treatment. Cancer Immunol Immunother. 2017;66:281–298.
   PubMed Web of Science ®Google Scholar
• Klebanoff CA, Acquavella N, Yu Z, et al. Therapeutic cancer vaccines: are we there yet? Immunol Rev. 2011;239:27–44.
   PubMed Web of Science ®Google Scholar
• Tang C, Wang X, Soh H, et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2:831–838.
   PubMed Web of Science ®Google Scholar
• Liao YP, Wang CC, Butterfield LH, et al. Ionizing radiation affects human MART-1 melanoma antigen processing and presentation by dendritic cells. J Immunol. 2004;173:2462–2469.
   PubMed Web of Science ®Google Scholar
• Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203:1259–1271.
   PubMed Web of Science ®Google Scholar
• Zhang B, Bowerman NA, Salama JK, et al. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med. 2007;204:49–55.
   PubMed Web of Science ®Google Scholar
• Frey B, Derer A, Scheithauer H, et al. Cancer cell death-inducing radiotherapy: Impact on local tumour control, tumour cell proliferation and induction of systemic anti-tumour immunity. Adv Exp Med Biol. 2016;930:151–172.
   PubMed Web of Science ®Google Scholar
• Wattenberg MM, Fahim A, Ahmed MM, et al. Unlocking the combination: potentiation of radiation-induced antitumor responses with immunotherapy. Radiat Res. 2014;182:126–138.
   PubMed Web of Science ®Google Scholar
• Demaria S, Bhardwaj N, McBride WH, et al. Combining radiotherapy and immunotherapy: a revived partnership. Int J Radiat Oncol Biol Phys. 2005;63:655–666.
   PubMed Web of Science ®Google Scholar
• Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–377.
   PubMed Web of Science ®Google Scholar
• Bernstein MB, Garnett CT, Zhang H, et al. Radiation-induced modulation of costimulatory and coinhibitory T-cell signaling molecules on human prostate carcinoma cells promotes productive antitumor immune interactions. Cancer Biother Radiopharm. 2014;29:153–161.
   PubMed Web of Science ®Google Scholar
• Kim JE, Patel MA, Mangraviti A, et al. Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results in regression of murine gliomas. Clin Cancer Res. 2017;23:124–136.
   PubMed Web of Science ®Google Scholar
• Verbrugge I, Gasparini A, Haynes NM, et al. The curative outcome of radioimmunotherapy in a mouse breast cancer model relies on mTOR signaling. Radiat Res. 2014;182:219–229.
   PubMed Web of Science ®Google Scholar
• Li X, Hu W, Zheng X, et al. Emerging immune checkpoints for cancer therapy. Acta Oncol. 2015;54:1706–1713.
   PubMed Web of Science ®Google Scholar
• Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161:205–214.
   PubMed Web of Science ®Google Scholar
• Elvington M, Scheiber M, Yang X, et al. Complement-dependent modulation of antitumor immunity following radiation therapy. Cell Rep. 2014;8:818–830.
   PubMed Web of Science ®Google Scholar
• Pilones KA, Kawashima N, Yang AM, et al. Invariant natural killer T cells regulate breast cancer response to radiation and CTLA-4 blockade. Clin Cancer Res. 2009;15:597–606.
   PubMed Web of Science ®Google Scholar
• Verbrugge I, Hagekyriakou J, Sharp LL, et al. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res. 2012;72:3163–3174.
   PubMed Web of Science ®Google Scholar
• Belcaid Z, Phallen JA, Zeng J, et al. Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLoS One. 2014;9:e101764.
   PubMed Web of Science ®Google Scholar
• Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11:728–734.
   PubMed Web of Science ®Google Scholar
• Park SS, Dong H, Liu X, et al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol Res. 2015;3:610–619.
   PubMed Web of Science ®Google Scholar
• Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687–695.
   PubMed Web of Science ®Google Scholar
• Wu CT, Chen WC, Chang YH, et al. The role of PD-L1 in the radiation response and clinical outcome for bladder cancer. Sci Rep. 2016;6:19740.
   PubMed Web of Science ®Google Scholar
• Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86:343–349.
   PubMed Web of Science ®Google Scholar
• Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74:5458–5468.
   PubMed Web of Science ®Google Scholar
• Young KH, Baird JR, Savage T, et al. Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS One. 2016;11:e0157164.
   PubMed Web of Science ®Google Scholar
• Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18:895–903.
   PubMed Web of Science ®Google Scholar
• Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377:1919–1929.
   PubMed Web of Science ®Google Scholar
• Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;Sept 25. Epub.
   Web of Science ®Google Scholar
• Koller KM, Mackley HB, Liu J, et al. Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Cancer Biol Ther. 2017;18:36–42.
   PubMed Web of Science ®Google Scholar
• Gameiro SR, Malamas AS, Bernstein MB, 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. Int J Radiat Oncol Biol Phys. 2016;95:120–130.
   PubMed Web of Science ®Google Scholar
• Ohkubo Y, Iwakawa M, Seino K, et al. Combining carbon ion radiotherapy and local injection of alpha-galactosylceramide-pulsed dendritic cells inhibits lung metastases in an in vivo murine model. Int J Radiat Oncol Biol Phys. 2010;78:1524–1531.
   PubMed Web of Science ®Google Scholar
• Ogata T, Teshima T, Kagawa K, et al. Particle irradiation suppresses metastatic potential of cancer cells. Cancer Res. 2005;65:113–120.
   PubMed Web of Science ®Google Scholar
• Matsunaga A, Ueda Y, Yamada S, et al. Carbon-ion beam treatment induces systemic antitumor immunity against murine squamous cell carcinoma. Cancer. 2010;116:3740–3748.
   PubMed Web of Science ®Google Scholar
• Shimokawa T, Ma L, Ando K, et al. The future of combining carbon-ion radiotherapy with immunotherapy: evidence and progress in mouse models. Int J Particle Ther 2016. 2016;3:61–70.
   PubMedGoogle Scholar
• Datta NR, Ordonez SG, Gaipl US, et al. Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future. Cancer Treat Rev. 2015;41:742–753.
   PubMed Web of Science ®Google Scholar
• Issels R, Kampmann E, Kanaar R, et al. Hallmarks of hyperthermia in driving the future of clinical hyperthermia as targeted therapy: translation into clinical application. Int J Hyperthermia. 2016;32:89–95.
   PubMed Web of Science ®Google Scholar
• Werthmoller N, Frey B, Ruckert M, et al. Combination of ionising radiation with hyperthermia increases the immunogenic potential of B16-F10 melanoma cells in vitro and in vivo. Int J Hyperthermia. 2016;32:23–30.
   PubMed Web of Science ®Google Scholar
• Knisely JP, Yu JB, Flanigan J, et al. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg. 2012;117:227–233.
   PubMed Web of Science ®Google Scholar
• Ahmed KA, Abuodeh YA, Echevarria MI, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol. 2016;27:2288–2294.
   PubMed Web of Science ®Google Scholar
• Bernstein MB, Krishnan S, Hodge JW, et al. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat Rev Clin Oncol. 2016;13:516–524.
   PubMed Web of Science ®Google Scholar
• Kalbasi A, June CH, Haas N, et al. Radiation and immunotherapy: a synergistic combination. J Clin Invest. 2013;123:2756–2763.
   PubMed Web of Science ®Google Scholar
• Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer. 2016;4:51.
   PubMed Web of Science ®Google Scholar
• Smyth MJ, Ngiow SF, Ribas A, et al. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016;13:143–158.
   PubMed Web of Science ®Google Scholar
• Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 2016;375:1767–1778.
   PubMed Web of Science ®Google Scholar
• Deloch L, Derer A, Hartmann J, et al. Modern radiotherapy concepts and the impact of radiation on immune activation. Front Oncol. 2016;6:141.
   PubMed Web of Science ®Google Scholar
• Frey B, Ruckert M, Weber J, et al. Hypofractionated irradiation has immune stimulatory potential and induces a timely restricted infiltration of immune cells in colon cancer tumors. Front Immunol. 2017;8:231.
   PubMed Web of Science ®Google Scholar
• Kulzer L, Rubner Y, Deloch L, et al. Norm- and hypo-fractionated radiotherapy is capable of activating human dendritic cells. J Immunotoxicol. 2014;11:328–336.
   PubMed Web of Science ®Google Scholar
• Brooks ED, Schoenhals JE, Tang C, et al. Stereotactic ablative radiation therapy combined with immunotherapy for solid tumors. Cancer J. 2016;22:257–266.
   PubMed Web of Science ®Google Scholar
• Popp I, Grosu AL, Niedermann G, et al. Immune modulation by hypofractionated stereotactic radiation therapy: therapeutic implications. Radiother Oncol. 2016;120:185–194.
   PubMed Web of Science ®Google Scholar
• Schoenhals JE, Seyedin SN, Tang C, et al. Preclinical rationale and clinical considerations for radiotherapy plus immunotherapy: going beyond local control. Cancer J. 2016;22:130–137.
   PubMed Web of Science ®Google Scholar
• Govindarajan R, Gujja S, Siegel ER, et al. Programmed cell death-ligand 1 (PD-L1) expression in anal cancer. Am J Clin Oncol. 2016;41:638–642.
   Web of Science ®Google Scholar
• Balermpas P, Martin D, Wieland U, et al. Human papilloma virus load and PD-1/PD-L1, CD8(+) and FOXP3 in anal cancer patients treated with chemoradiotherapy: rationale for immunotherapy. Oncoimmunology. 2017;6:e1288331.
   PubMed Web of Science ®Google Scholar
• Martin D, Rodel F, Balermpas P, et al. The immune microenvironment and HPV in anal cancer: Rationale to complement chemoradiation with immunotherapy. Biochim Biophys Acta Rev Cancer. 2017;1868:221–230.
   PubMed Web of Science ®Google Scholar
• Joe MB, Lum JJ, Watson PH, et al. Radiation generates an abscopal response and complete resolution of metastatic squamous cell carcinoma of the anal canal: a case report. J Gastrointest Oncol. 2017;8:E84–E89.
   PubMed Web of Science ®Google Scholar
• Morris VK, Salem ME, Nimeiri H, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18:446–453.
   Web of Science ®Google Scholar
• Dale JE, Sebjornsen S, Leh S, et al. Multimodal therapy is feasible in elderly anal cancer patients. Acta Oncol. 2017;56:81–87.
   PubMed Web of Science ®Google Scholar
• Leon O, Guren M, Hagberg O, et al. Anal carcinoma - survival and recurrence in a large cohort of patients treated according to Nordic guidelines. Radiother Oncol. 2014;113:352–358.
   PubMed Web of Science ®Google Scholar
• Ebner DK, Kamada T, Yamada S. Abscopal effect in recurrent colorectal cancer treated with carbon-ion radiation therapy: 2 case reports. Adv Radiat Oncol. 2017;2:333–338.
   PubMedGoogle Scholar
• Fujita M, Imadome K, Shoji Y, et al. Carbon-ion irradiation suppresses migration and invasiveness of human pancreatic carcinoma cells MIAPaCa-2 via Rac1 and RhoA degradation. Int J Radiat Oncol Biol Phys. 2015;93:173–180.
   PubMed Web of Science ®Google Scholar
• Cobianchi L, Fossati P, Peloso A, et al. Carbon ion radiotherapy and completion pancreatectomy. A feasible model to explore a new integrated approach? Pancreatology. 2017;17:19–21.
   PubMed Web of Science ®Google Scholar
• Shinoto M, Yamada S, Terashima K, et al. Carbon ion radiation therapy with concurrent gemcitabine for patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2016;95:498–504.
   PubMed Web of Science ®Google Scholar
• Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15:5379–5388.
   PubMed Web of Science ®Google Scholar
• Yoshimoto Y, Suzuki Y, Mimura K, et al. Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model. PLoS One. 2014;9:e92572.
   PubMed Web of Science ®Google Scholar
• Azad A, Yin Lim S, D'Costa Z, et al. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med. 2017;9:167–180.
   PubMed Web of Science ®Google Scholar
• Stamell EF, Wolchok JD, Gnjatic S, et al. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys. 2013;85:293–295.
   PubMed Web of Science ®Google Scholar
• Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1:365–372.
   PubMed Web of Science ®Google Scholar
• Slovin SF, Higano CS, Hamid O, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24:1813–1821.
   PubMed Web of Science ®Google Scholar
• Mathew M, Tam M, Ott PA, et al. Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res. 2013;23:191–195.
   PubMed Web of Science ®Google Scholar
• Barker CA, Postow MA, Khan SA, et al. Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol Res. 2013;1:92–98.
   PubMed Web of Science ®Google Scholar
• Silk AW, Bassetti MF, West BT, et al. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med. 2013;2:899–906.
   PubMed Web of Science ®Google Scholar
• Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700–712.
   PubMed Web of Science ®Google Scholar
• Kiess AP, Wolchok JD, Barker CA, et al. Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys. 2015;92:368–375.
   PubMed Web of Science ®Google Scholar
• Patel KR, Shoukat S, Oliver DE, et al. Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases. Am J Clin Oncol 2015;40:444–450.
   Web of Science ®Google Scholar
• Qin R, Olson A, Singh B, et al. Safety and efficacy of radiation therapy in advanced melanoma patients treated with ipilimumab. Int J Radiat Oncol Biol Phys. 2016;96:72–77.
   PubMed Web of Science ®Google Scholar
• Hiniker SM, Reddy SA, Maecker HT, et al. A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Int J Radiat Oncol Biol Phys. 2016;96:578–588.
   PubMed Web of Science ®Google Scholar
• Kropp LM, De Los Santos JF, McKee SB, et al. Radiotherapy to control limited melanoma progression following ipilimumab. J Immunother. 2016;39:373–378.
   PubMed Web of Science ®Google Scholar
• Levy A, Massard C, Soria JC, et al. Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: single centre subset analysis from a phase 1/2 trial. Eur J Cancer. 2016;68:156–162.
   PubMed Web of Science ®Google Scholar
• Ahmed KA, Kim S, Arrington J, et al. Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases. J Neurooncol. 2017;133:331–338.
   PubMed Web of Science ®Google Scholar
• Williams NL, Wuthrick EJ, Kim H, et al. Phase 1 study of ipilimumab combined with whole brain radiation therapy or radiosurgery for melanoma patients with brain metastases. Int J Radiat Oncol Biol Phys. 2017;99:22–30.
   PubMed Web of Science ®Google Scholar
• Pike LRG, Bang A, Ott P, et al. Radiation and PD-1 inhibition: favorable outcomes after brain-directed radiation. Radiother Oncol. 2017;124:98–103.
   PubMed Web of Science ®Google Scholar