Research progress on stereotactic radiotherapy combined with immunotherapy for malignancies
Zhu Xiaopeng1,2, Liu Bailong1, Li Cheng1, Lv Jincai1, Quan Xiaoyue1, Liu Min1, Dong Lihua1
1.Department of Radiation Oncology,First Hospital of Jilin University,Changchun 130021,China;2.Cancer center,First Affiliated Hospital,Xinjiang Medical University,Urumqi 830011,China
Abstract：Surgery, radiotherapy and chemotherapy are three traditional treatments for malignant tumors. With the development of medicine, immunotherapy has been gradually adopted as an emerging therapy of malignancies. Recent clinical studies have demonstrated that the combination of radiotherapy and immunotherapy can induce the abscopal effect and improve the prognosis of patients. Compared with the conventional radiotherapy, stereotactic radiotherapy has a larger single dose and higher accuracy, which is more likely to induce the bystander effect and anti-tumor response. The combination of stereotactic radiotherapy and immunotherapy has been proven to be a more promising therapy in certain clinical trials. However, not all types of tumors can benefit from such combined therapy in clinical practice. The optimal dose, fraction pattern and lesion of radiotherapy, immune enhancement and safety remain to be further clarified. In this article, the research progress, related controversies and future research direction of stereotactic radiotherapy combined with immunotherapy for malignancies were reviewed.
Zhu Xiaopeng,Liu Bailong,Li Cheng et al. Research progress on stereotactic radiotherapy combined with immunotherapy for malignancies[J]. Chinese Journal of Radiation Oncology, 2019, 28(5): 389-393.
[1]Bernstein MB,Krishnan S,Hodge JW,et al. Immunotherapy and stereotactic ablative radiotherapy (ISABR):a curative approach?[J].Nat Rev Clin Oncol,2016,13(8):516-524.DOI:10.1038/nrclinonc.2016.30. [2]Younes E,Haas GP,Dezso B,et al. Local tumor irradiation augments the response to IL-2 therapy in a murine renal adenocarcinoma[J].Cell Immunol,1995,165(2):243-51.DOI:10.1006/cimm.1995.1211. [3]Haikerwal SJ,Hagekyriakou J,MacManus M,et al. Building immunity to cancer with radiation therapy[J].Cancer Lett,2015,368(2):198-208.DOI:10.1016/j.canlet.2015.01.009. [4]Brown JM.The hypoxic cell:a target for selective cancer therapy-eighteenth Bruce F.Cain memorial award lecture[J].Cancer Res,1999,59(23):5863-5870. [5]Schaue D,Ratikan JA,Iwamoto KS,et al. Maximizing tumor immunity with fractionated radiation[J].Int J Radiat Oncol Biol Phys,2012,83(4):1306-1310.DOI:10.1016/j.ijrobp.2011.09.049. [6]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[J].Clin Cancer Res,2009,15(17):5379-5388.DOI:10.1158/1078-0432.ccr-09-0265. [7]Twyman-Saint VC,Rech AJ,Maity A,et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer[J].Nature,2015,520(7547):373-377.DOI:10.1038/nature14292. [8]van den Heuvel MM,Verheij M,Boshuizen R,et al. NHS-IL2 combined with radiotherapy:preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy[J].J Transl Med,2015,13(1):32.DOI:10.1186/s12967-015-0397-0. [9]Reynders K,Illidge T,Siva S,et al. The abscopal effect of local radiotherapy:using immunotherapy to make a rare event clinically relevant[J].Cancer Treat Rev,2015,41(6):503-510.DOI:10.1016/j.ctrv.2015.03.011. [10]Abuodeh Y,Venkat P,Kim S.Systematic review of case reports on the abscopal effect[J].Curr Probl Cancer,2016,40(1):25-37.DOI:10.1016/j.currproblcancer.2015.10.001. [11]Kumar T,Patel N,Talwar A.Spontaneous regression of thoracic malignancies[J].Respir Med,2010,104(10):1543-1550.DOI:10.1016/j.rmed.2010.04.026. [12]Demaria S,Ng B,Devitt ML,et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated[J].Int J Radiat Oncol Biol Phys,2004,58(3):862-870.DOI:10.1016/j.ijrobp.2003.09.012. [13]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[J].Cancer Immunol Res,2013,1(6):365-372.DOI:10.1158/2326-6066.cir-13-0115. [14]Gameiro SR,Ardiani A,Kwilas A,et al. Radiation-induced survival responses promote immunogenic modulation to enhance immunotherapy in combinatorial regimens[J].Oncoimmunology,2014,3:e28643.DOI:10.4161/onci.28643. [15]Kepp O,Senovilla L,Vitale I,et al. Consensus guidelines for the detection of immunogenic cell death[J].Oncoimmunology,2014,3(9):e955691.DOI:10.4161/21624011.2014.955691. [16]Snyder A,Makarov V,Merghoub T,et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma[J].N Engl J Med,2014,371(23):2189-2199.DOI:10.1056/NEJMoa1406498. [17]Rosenberg JE,Hoffman-Censits J,Powles T,et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy:a single-arm,multicentre,phase 2 trial[J].Lancet,2016,387(10031):1909-1920.DOI:10.1016/s0140-6736(16)00561-4. [18]Kalbasi A,June CH,Haas N,et al. Radiation and immunotherapy:a synergistic combination[J].J Clin Invest,2013,123(7):2756-2763.DOI:10.1172/jci69219. [19]Novak N,Bieber T.2.Dendritic cells as regulators of immunity and tolerance[J].J Allergy Clin Immunol,2008,121(2 Suppl):S370-374,S413.DOI:10.1016/j.jaci.2007.06.001. [20]El Chediak A,Shamseddine A,Bodgi L,et al. Optimizing tumor immune response through combination of radiation and immunotherapy[J].Med Oncol,2017,34(9):165.DOI:10.1007/s12032-017-1025-z. [21]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[J].Lancet Oncol,2015,16(7):795-803.DOI:10.1016/s1470-2045(15)00054-6. [22]Barker CA,Postow MA.Combinations of radiation therapy and immunotherapy for melanoma:a review of clinical outcomes[J].Int J Radiat Oncol Biol Phys,2014,88(5):986-997.DOI:10.1016/j.ijrobp.2013.08.035. [23]Begley CG,Burton JD,Tsudo M,et al. Human B lymphocytes express the p75 component of the interleukin 2 receptor[J].Leuk Res,1990,14(3):263-271. [24]Yasuda K,Nirei T,Tsuno NH,et al. Intratumoral injection of interleukin-2 augments the local and abscopal effects of radiotherapy in murine rectal cancer[J].Cancer Sci,2011,102(7):1257-1263.DOI:10.1111/j.1349-7006.2011.01940.x. [25]Seung SK,Curti BD,Crittenden M,et al. Phase 1 study of stereotactic body radiotherapy and interleukin-2—tumor and immunological responses[J].Sci Transl Med,2012,4(137):137ra74.DOI:10.1126/scitranslmed.3003649. [26]Gough MJ,Crittenden MR,Sarff M,et al. Adjuvant therapy with agonistic antibodies to CD134(OX40) increases local control after surgical or radiation therapy of cancer in mice[J].J Immunother,2010,33(8):798-809.DOI:10.1097/CJI.0b013e3181ee7095. [27]Linn YC,Hui KM.Cytokine-induced NK-like T cells:from bench to bedside[J].J Biomed Biotechnol,2010,2010:435745.DOI:10.1155/2010/435745. [28]Verneris MR,Baker J,Edinger M,et al. Studies of ex vivo activated and expanded CD8+ NK-T cells in humans and mice[J].J Clin Immunol,2002,22(3):131-136. [29]Wang YS,Yang G,Wang YY,et al. Early efficacy of stereotactic body radiation therapy combined with adoptive immunotherapy for advanced malignancies[J].Mol Clin Oncol,2013,1(5):925-929.DOI:10.3892/mco.2013.157. [30]Wang YY,Wang YS,Liu T,et al. Efficacy study of CyberKnife stereotactic radiosurgery combined with CIK cell immunotherapy for advanced refractory lung cancer[J].Exp Ther Med,2013,5(2):453-456.DOI:10.3892/etm.2012.818. [31]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[J].Lancet Oncol,2017,18(7):895-903.DOI:10.1016/s1470-2045(17)30380-7. [32]Barker CA,Postow MA,Khan SA,et al. Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma[J].Cancer Immunol Res,2013,1(2):92-98.DOI:10.1158/2326-6066.cir-13-0082. [33]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[J].Int J Radiat Oncol Biol Phys,2015,92(2):368-375.DOI:10.1016/j.ijrobp.2015.01.004. [34]Patel KR,Shoukat S,Oliver DE,et al. Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases[J].Am J Clin Oncol,2017,40(5):444-450.DOI:10.1097/coc.0000000000000199. [35]Hiniker SM,Reddy SA,Maecker HT,et al. A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma[J].Int J Radiat Oncol Biol Phys,2016,96(3):578-588.DOI:10.1016/j.ijrobp.2016.07.005. [36]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[J].Ann Oncol,2013,24(7):1813-1821.DOI:10.1093/annonc/mdt107. [37]Luke JJ,Lemons JM,Karrison TG,et al. Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors[J].J Clin Oncol,2018,36(16):1611-1618.DOI:10.1200/jco.2017.76.2229. [38]Sharabi AB,Lim M,DeWeese TL,et al. Radiation and checkpoint blockade immunotherapy:radiosensitisation and potential mechanisms of synergy[J].Lancet Oncol,2015,16(13):e498-509.DOI:10.1016/s1470-2045(15)00007-8. [39]Johnson DB,Balko JM,Compton ML,et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade[J].N Engl J Med,2016,375(18):1749-1755.DOI:10.1056/NEJMoa1609214. [40]Moslehi JJ,Salem JE,Sosman JA,et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis[J].Lancet,2018,391(10124):933.DOI:10.1016/s0140-6736(18)30533-6.
2019, Vol. 28 
