Abstract: Immune checkpoint blockade can promote the tumor-specific cytotoxic T-lymphocyte (CTL) response. However, only a small proportion of patients have good response to immune checkpoint blockade. It has been reported that radiotherapy combined with immune checkpoint blockade can promote antigen presentation, which further enhances the tumor-specific CTL response;moreover, the combined therapy achieves better treatment outcomes than radiotherapy alone or immune checkpoint blockade alone. The latest study has shown that radiotherapy combined with dual immune checkpoint blockade has better efficacy than radiotherapy combined with CTLA-4 blockade in patients with melanoma. Therefore, radiotherapy combined with immune checkpoint blockade will become a new approach for treating tumor. This paper reviews the research advances in the combined therapy.
Song Xing,Pei Honglei. Research advances in radiotherapy combined with immune checkpoint blockade[J]. Chinese Journal of Radiation Oncology, 2017, 26(3): 348-351.
[1] Mahoney KM,Rennert PD,Freeman GJ.Combination cancer immunotherapy and new immunomodulatory targets[J].Nat Rev Drug Discov,2015,14(8):561-584.DOI:10.1038/nrd4591. [2] Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy[J].Nat Rev Cancer,2012,12(4):252-264.DOI:10.1038/nrc3239. [3] Lee Y,Auh SL,Wang YG,et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells:changing strategies for cancer treatment[J].Blood,2009,114(3):589-595.DOI:10.1182/blood-2009-02-206870. [4] Deng LF,Liang H,Burnette B,et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice[J].J Clin Invest,2014,124(2):687-695.DOI:10.1172/JCI67313. [5] van Elsas A,Hurwitz AA,Allison JP.Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4(CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation[J].J Exp Med,1999,190(3):355-366.DOI:10.1084/jem.190.3.355. [6] Frey B,Rubner Y,Wunderlich R,et al. Induction of abscopal anti-tumor immunity and immunogenic tumor cell death by ionizing irradiation-implications for cancer therapies[J].Curr Med Chem,2012,19(12):1751-1764.DOI:10.2174/092986712800099811. [7] Brahmer JR,Tykodi SS,Chow LQM,et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J].New Engl J Med,2012,366(26):2455-2465.DOI:10.1056/NEJMoa1200694. [8] Liang SC,Latchman YE,Buhlmann JE,et al. Regulation of PD-1,PD-L1,and PD-L2 expression during normal and autoimmune responses[J].Eur J Immunol,2003,33(10):2706-2716.DOI:10.1002/eji.200324228. [9] Hirahara K,Ghoreschi K,Yang XP,et al. Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1[J].Immunity,2012,36(6):1017-1030.DOI:10.1016/j.immuni.2012.03.024. [10] Dong HD,Strome SE,Salomao DR,et al. Tumor-associated B7-H1 promotes T-cell apoptosis:a potential mechanism of immune evasion[J].Nat Med,2002,8(8):793-800.DOI:10.1038/nm730. [11] Robert C,Ribas A,Wolchok JD,et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma:a randomised dose-comparison cohort of a phase 1 trial[J].Lancet,2014,384(9948):1109-1117.DOI:10.1016/S0140-6736(14)60958-2. [12] Powles T,Eder JP,Fine GD,et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer[J].Nature,2014,515(7528):558-562.DOI:10.1038/nature13904. [13] Wherry EJ.T cell exhaustion[J].Nat Immunol,2011,12(6):492-499.DOI:10.1038/ni.2035. [14] Victor CTS,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. [15] Park SS,Dong HD,Liu X,et al. PD-1 restrains radiotherapy-induced abscopal effect[J].Cancer Immunol Res,2015,3(6):610-619.DOI:10.1158/2326-6066.CIR-14-0138. [16] Zeng J,See AP,Phallen J,et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas[J].Int J Radiat Oncol Biol Phys,2013,86(2):343-349.DOI:10.1016/j.ijrobp.2012.12.025. [17] Burnette BC,Liang H,Lee Y,et al. The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity[J].Cancer Res,2011,71(7):2488-2496.DOI:10.1158/0008-5472.CAN-10-2820. [18] 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[J].Clin Cancer Res,2005,11(2 Pt 1):728-734. [19] Postow MA,Callahan MK,Barker CA,et al. Immunologic correlates of the abscopal effect in a patient with melanoma[J].New Engl J Med,2012,366(10):925-931.DOI:10.1056/NEJMoa1112824. [20] 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. [21] 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[J].Lancet Oncol,2014,15(7):700-712.DOI:10.1016/S1470-2045(14)70189-5. [22] Postow MA,Chesney J,Pavlick AC,et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma[J].New Engl J Med,2015,372(21):2006-2017.DOI:10.1056/NEJMoa1414428. [23] 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. [24] Dovedi SJ,Adlard AL,Lipowska-Bhalla G,et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade[J].Cancer Res,2014,74(19):5458-5468.DOI:10.1158/0008-5472.CAN-14-1258. [25] 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. [26] Wolchok JD,Kluger H,Callahan MK,et al. Nivolumab plus ipilimumab in advanced melanoma[J].New Engl J Med,2013,369(2):122-133.DOI:10.1056/NEJMoa1302369. [27] Roberts CM,Foulcher E,Zaunders JJ,et al. Radiation pneumonitis:a possible lymphocyte-mediated hypersensitivity reaction[J].Ann Int Med,1993,118(9):696-700.DOI:10.7326/0003-4819-118-9-199305010-00006. [28] Nakamura M,Hirooka Y,Watanabe O,et al. Three cases with active bleeding from radiation enteritis that were diagnosed with video capsule endoscopy without retention[J].Nagoya J Med Sci,2014,76(3-4):369-374. [29] Morgan GW,Breit SN.Radiation and the lung:a reevaluation of the mechanisms mediating pulmonary injury[J].Int J Radiat Oncol Biol Phys,1995,31(2):361-369.DOI:10.1016/0360-3016(94)00477-3.