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A review of radiation induced abscopal effect: combining radiotherapy and immunotherapy to treat the untreated distant metastatic tumours

Published online by Cambridge University Press:  08 September 2020

Ernest Osei*
Affiliation:
Department of Medical Physics, Grand River Regional Cancer Centre, Kitchener, ON, Canada Department of Physics and Astronomy Department of Systems Design Engineering Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
Ruth Francis
Affiliation:
Department of Medical Physics, Grand River Regional Cancer Centre, Kitchener, ON, Canada Department of Biology, University of Waterloo, Waterloo, ON, Canada
Lyba Sheraz
Affiliation:
Department of Medical Physics, Grand River Regional Cancer Centre, Kitchener, ON, Canada Faculty of Science, School of Interdisciplinary Science, McMaster University, Hamilton, ON, Canada
*
Author for correspondence: Ernest Osei, Grand River Regional Cancer Centre, Medical Physics, 835 King Street West, Kitchener, ONN2G1G3, Canada. E-mail: [email protected]

Abstract

Background:

Radiotherapy is an effective and significant mode of definitive cancer treatment with well-established local tumour control success, especially in the treatment of localised tumours. Although, for metastatic disease, the role of radiotherapy has generally been limited to palliation of symptoms. In the treatment of metastatic diseases settings, the radiation therapy technique has always been confronted with the challenge of the simultaneous treatment of all of the various distant metastatic tumour sites, however, some recent evidence suggests that radiotherapy can potentially induce anticancer immune responses whose effectors potentially migrate to distant metastatic tumours to provoke their regression in cancer patients. Thus, unirradiated distant metastatic tumour sites can exhibit a delayed therapeutic response termed the abscopal effect.

Materials and methods:

This paper reports on a review of the abscopal effect, including its biological mechanism, the effect of radiation dose and fractionation regime and the timing of immunotherapy administration on radiotherapy-induced abscopal effect, the enhancement of radiotherapy-induced abscopal effects with immunotherapy, the effect of the location of the irradiated tumour and the radiotherapy of multiple tumour sites on the likelihood and effectiveness of inducing abscopal responses in the preclinical and clinical settings and also reports on some evidence of clinical observations in patients.

Conclusions:

Although abscopal effects of radiotherapy are still relatively rare in patients, it has gained a lot of interest due to recent development and use of immunotherapy strategies incorporating combinations of targeted immunomodulators and immune checkpoint blockade with radiation therapy. The enhancement of cancer immunotherapy could potentially enable the translation of the concept of abscopal effect into the clinics as a new strategy to induce therapeutically effective anti-tumour immune responses in cancer patients. The combination of radiotherapy and immunotherapy has the potential to expand the role of radiotherapy from a purely local tumour control treatment to play a significant role in advanced and metastatic tumour control and this could likely lead to a paradigm shift in the treatment of patients with metastatic cancer.

Type
Literature Review
Copyright
© The Author(s), 2020. Published by Cambridge University Press

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References

Xu, L, Osei, B, Osei, E. A review of radiation genomics: integrating patient radiation response with genomics for personalised and targeted radiation therapy. J Radiother Pract 2019; 18(2): 198209.CrossRefGoogle Scholar
Yap, ML, Zubizarreta, E, Bray, F, Ferlay, J, Barton, M. Global access to radiotherapy services: have we made progress during the past decade? 2016; 2(4): 207215.Google ScholarPubMed
Darko, J, Osei, E, Fleck, A, Rachakonda, R. Retrospective dosimetric evaluation of VMAT plans for prostate cancer treatment. J Radiother Pract 2019; 18(2): 155164.CrossRefGoogle Scholar
Osei, E, Mansoor, H, Darko, J, Osei, B, Fleming, K, Rachakonda, R. Dosimetric evaluation of whole-pelvis radiation therapy of prostate cancers: clinical experience. J Radiother Pract 2020: 115.Google Scholar
Yilmaz, MT, Elmali, A, Yazici, G. Abscopal effect, from myth to reality: from radiation oncologists’ perspective. Cureus 2019; 11(1): e3860.Google ScholarPubMed
Marín, A, Martín, M, Liñán, O, et al. Bystander effects and radiotherapy. Rep Pract Oncol Radiother 2014; 20(1): 1221.CrossRefGoogle ScholarPubMed
Najafi, M, Fardid, R, Hadadi, G, Fardid, M. The mechanisms of radiation-induced bystander effect. J Biomed Phys Eng 2014; 4(4): 163172.Google ScholarPubMed
Rödel, F, Frey, B, Multhoff, G, Gaipl, U. Contribution of the immune system to bystander and non-targeted effects of ionizing radiation. Cancer Lett 2013; 356(1): 105113.CrossRefGoogle ScholarPubMed
Habets, TH, Oth, T, Houben, AW, et al. Fractionated radiotherapy with 3 x 8 Gy induces systemic anti-tumour responses and abscopal tumour inhibition without modulating the humoral anti-tumour response. PLoS One 2016; 11(7): e0159515. doi: 10.1371/journal.pone.0159515 CrossRefGoogle ScholarPubMed
Lakshmanagowda, PB, Viswanath, L, Thimmaiah, N, Dasappa, L, Supe, SS, Kallur, P. Abscopal effect in a patient with chronic lymphocytic leukemia during radiation therapy: a case report. Cases J 2009; 2: 204.CrossRefGoogle Scholar
Kroemer, G, Zitvogel, L. Abscopal but desirable. OncoImmunology 2012; 1(4): 407408.CrossRefGoogle ScholarPubMed
Dewan, ZM, 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. 2009; 15(17): 53795388. doi: 10.1158/1078-0432.CCR-09-0265 Google Scholar
Ng, J, Dai, T. Radiation therapy and the abscopal effect: a concept comes of age. Ann Transl Med 2016; 4(6): 118.CrossRefGoogle ScholarPubMed
Demaria, S, Formenti, SC. Can abscopal effects of local radiotherapy be predicted by modeling T cell trafficking? J Immunother Cancer 2016; 4(1): 29.CrossRefGoogle ScholarPubMed
Suek, N, Campesato, LF, Merghoub, T, Khalil, DN. Targeted APC activation in cancer immunotherapy to enhance the abscopal effect. Front Immunol 2019; 10: 604.CrossRefGoogle ScholarPubMed
Azami, A, Suzuki, N, Azami, Y, et al. Abscopal effect following radiation monotherapy in breast cancer: a case report. Mol Clin Oncol 2018; 9(3): 283286.Google ScholarPubMed
Brenneman, RJ, Sharifai, N, Fischer-Valuck, B, et al. Abscopal effect following proton beam radiotherapy in a patient with inoperable metastatic retroperitoneal sarcoma. Front Oncol 2019; 9: Article 922, 19.CrossRefGoogle Scholar
Britschgi, C, Riesterer, O, Burger, IA, Guckenberger, M, Curioni-Fontecedro, A. Report of an abscopal effect induced by stereotactic body radiotherapy and nivolumab in a patient with metastatic non-small cell lung cancer. Radiat Oncol 2018; 13(1): 102.CrossRefGoogle Scholar
Garelli, E, Rittmeyer, A, Putora, PM, Glatzer, M, Dressel, R, Andreas, S. Abscopal effect in lung cancer: three case reports and a concise review. Immunotherapy 2019; 11(17): 14451461.CrossRefGoogle Scholar
Nam, SW, Han, J, Kim, JI, et al. Spontaneous regression of a large hepatocellular carcinoma with skull metastasis. J Gastroenterol Hepatol 2005; 20(3): 488492.CrossRefGoogle ScholarPubMed
Golden, EB, Chhabra, A, Chachoua, A, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 2015; 16(7): 795803.CrossRefGoogle ScholarPubMed
Formenti, SC, Demaria, S. Combining radiotherapy and cancer immunotherapy: a paradigm shift.J Nat Cancer Inst 2013; 105(4): 256265.10.1093/jnci/djs629CrossRefGoogle ScholarPubMed
Formenti, SC, Demaria, S. Systemic effects of local radiotherapy. Lancet Oncol 2009; 10: 718726.CrossRefGoogle ScholarPubMed
Frey, B, Rückert, M, Weber, J, et al. Hypofractionated irradiation has immune stimulatory potential and induces a timely restricted infiltration of immune cells in colon cancer tumors. 2017; Available at: https://nbn-resolving.org/urn:nbn:de:bvb:29-opus4-94429. Accessed 18th June 2020.CrossRefGoogle Scholar
Sharabi, AB, Lim, M, DeWeese, TL, Drake, CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 2015; 16(13): e498e509.CrossRefGoogle ScholarPubMed
Shi, F, Wang, X, Teng, F, Kong, L, Yu, J. Abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte-macrophage colony-stimulating factor therapy. Cancer Biol Ther 2017; 18(3): 137141.CrossRefGoogle ScholarPubMed
Levy, A, Chargari, C, Marabelle, A, Perfettini, J, Magné, N, Deutsch, E. Can immunostimulatory agents enhance the abscopal effect of radiotherapy? Eur J Cancer 2016; 62: 3645.CrossRefGoogle ScholarPubMed
Ngwa, W, Irabor, OC, Schoenfeld, JD, Hesser, J, Demaria, S, Formenti, SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer 2018; 18(5): 313322.CrossRefGoogle ScholarPubMed
Trommer, M, Yeo, SY, Persigehl, T, et al. Abscopal effects in radio-immunotherapy-response analysis of metastatic cancer patients with progressive disease under anti-PD-1 immune checkpoint inhibition. Front Pharmacol 2019; 10(511): 1615.CrossRefGoogle ScholarPubMed
Buchwald, ZS, Wynne, J, Nasti, TH, et al. Radiation, immune checkpoint blockade and the abscopal effect: a critical review on timing, dose and fractionation. Front Oncol 2018; 8: 612.CrossRefGoogle ScholarPubMed
Tubin, S, Gupta, S, Mansoor, A. Clinical utilization of the radiation-hypoxia-induced abscopal/bystander effect in lung cancer. Radiother Oncol 2017; 123(s1): S539S540.CrossRefGoogle Scholar
Wu, C, Chen, W, Chen, M. The response of prostate cancer to androgen deprivation and irradiation due to immune modulation. Cancers 2018; 11(1): 20.CrossRefGoogle ScholarPubMed
Poleszczuk, JT, Luddy, KA, Prokopiou, S, et al. Abscopal benefits of localized radiotherapy depend on activated T-cell trafficking and distribution between metastatic lesions. Cancer Res 2016; 76(5): 10091018.CrossRefGoogle ScholarPubMed
Hu, Z, McArthur, H, Ho, A. The abscopal effect of radiation therapy: what is it and how can we use it in breast cancer? Curr Breast Cancer Rep 2017; 9(1): 4551.CrossRefGoogle ScholarPubMed
Zhang, X, Niedermann, G. Abscopal effects with hypofractionated schedules extending into the effector phase of the tumor-specific T-cell response. Int J Radiat Oncol Biol Phys 2018; 101(1): 6373.CrossRefGoogle ScholarPubMed
Morisada, M, Clavijo, PE, Moore, E, et al. PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation. OncoImmunology 2017; 7(3): e1395996.CrossRefGoogle Scholar
Lugade, AA, Moran, JP, Gerber, SA, Rose, RC, Frelinger, JG, Lord, EM. 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(12): 75167523.CrossRefGoogle ScholarPubMed
Schaue, D, Ratikan, JA, Iwamoto, KS, McBride, WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys 2012; 83(4): 13061310.CrossRefGoogle ScholarPubMed
Kulzer, L, Rubner, Y, Deloch, L, et al. Norm- and hypo-fractionated radiotherapy is capable of activating human dendritic cells. J Immunotoxicol 2014; 11(4): 328336.CrossRefGoogle ScholarPubMed
Derer, A, Spiljar, M, Bäumler, M, et al. Chemoradiation increases PD-L1 expression in certain melanoma and glioblastoma cells. Front Immunol 2016; 7: 610.CrossRefGoogle ScholarPubMed
Tang, C, Welsh, JW, de Groot, P, et al. Ipilimumab with stereotactic ablative radiation therapy: phase I results and immunologic correlates from peripheral T cells. Clin Cancer Res 2017; 23(6): 13881396.CrossRefGoogle ScholarPubMed
Brooks, ED, Chang, JY. Time to abandon single-site irradiation for inducing abscopal effects. Nat Rev Clin Oncol 2019; 16(2): 123135.CrossRefGoogle ScholarPubMed
Heppner, GH, Shekhar, M. Tumor heterogeneity is fundamental to the tumor ecosystem. Oncology (Williston Park) 2014; 28(9): 780.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(6): e0157164.CrossRefGoogle ScholarPubMed
Wang, L, He, L, Bao, G, He, X, Fan, S, Wang, H. Ionizing radiation induces HMGB1 cytoplasmic translocation and extracellular release. Int J Radiat Med Nucl Med 2016; 40(2): 9199.Google ScholarPubMed
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(19): 54585468.CrossRefGoogle ScholarPubMed
Hettich, M, Lahoti, J, Prasad, S, Niedermann, G. Checkpoint antibodies but not T cell-recruiting diabodies effectively synergize with TIL-inducing γ-irradiation. Cancer Res 2016; 76(16): 46734683.CrossRefGoogle ScholarPubMed
Morales-Orue, I, Chicas-Sett, R, Lara, PC. Nanoparticles as a promising method to enhance the abscopal effect in the era of new targeted therapies. Rep Pract Oncol Radiother 2019; 24(1): 8691.CrossRefGoogle ScholarPubMed
Park, SS, Dong, H, Liu, X, et al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol Res 2015; 3(6): 610619.CrossRefGoogle ScholarPubMed
Vanpouille-Box, C, Alard, A, Aryankalayil, MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 2017; 8(1): 15618.CrossRefGoogle ScholarPubMed
Wu, L, Wu, MO, La Maza, L, et al. Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model. Oncotarget 2015; 6(14): 1246812480.CrossRefGoogle Scholar
Golden, EB, Demaria, S, Schiff, PB, Chachoua, A, Formenti, SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 2013; 1(6): 365372.CrossRefGoogle Scholar
Demaria, S, Pilones, KA, Formenti, SC, Dustin, ML. Exploiting the stress response to radiation to sensitize poorly immunogenic tumors to anti-CTLA-4 treatment. OncoImmunology 2013; 2(3): e23127.CrossRefGoogle ScholarPubMed
Formenti, SC, Rudqvist, N, Golden, E, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 2018; 24(12): 18451851.CrossRefGoogle ScholarPubMed
Pitt, JM, Kroemer, G, Zitvogel, L. Immunogenic and non-immunogenic cell death in the tumor microenvironment. Adv Exp Med Biol 2017; 1036: 6579.CrossRefGoogle ScholarPubMed