[an error occurred while processing this directive]|[an error occurred while processing this directive]
放疗联合CTLA-4单抗的机制与临床研究进展
张致远, 夏凡, 章真
复旦大学附属肿瘤医院放疗科 复旦大学上海医学院肿瘤学系200032
Research progress on combined treatment of radiotherapy and anti-CTLA-4 antibody
Zhang Zhiyuan, Xia Fan, Zhang Zhen
Department of Radiation Oncology, Fudan University Shanghai Cancer Center;Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Abstract：Radiotherapy (RT) is one of the three prevailing therapeutics for tumors. With rapid development of immunotherapy (IM), the combination of IM and RT has gainned increasingly widespread attention. Cytotoxic T lymphocyte associated protein-4(CTLA-4) inhibitor is an important checkpoint target in immune activation and regulation, which exerts significant anti-tumor effects in melanoma and non-small cell lung cancer, etc. Accordingly, the combination of RT and anti-CTLA-4 antibody has become a hot spot. This article reviews research progress on pre-clinical and clinical evidences of RT combined with anti-CTLA-4 antibody, which provides evidence for further exploration in this field.
Zhang Zhiyuan,Xia Fan,Zhang Zhen. Research progress on combined treatment of radiotherapy and anti-CTLA-4 antibody[J]. Chinese Journal of Radiation Oncology, 2021, 30(9): 975-978.
[1] Schaue D, Micewicz ED, Ratikan JA, et al.Radiation and inflammation[J]. Semin Radiat Oncol, 2015, 25(1):4-10.DOI:10.1016/j.semradonc.2014.07.007. [2] Ribas A, Wolchok JD.Cancer immunotherapy using checkpoint blockade[J]. Science, 2018, 359(6382):1350-1355.DOI:10.1126/science.aar4060. [3] Jain N, Nguyen H, Chambers C, et al.Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity[J]. Proc Natl Acad Sci USA, 2010, 107(4):1524-1528.DOI:10.1073/pnas.0910341107. [4] Simpson TR, Li F, Montalvo-Ortiz W, et al.Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma[J]. J Exp Med, 2013, 210(9):1695-1710.DOI:10.1084/jem.20130579. [5] Arce Vargas F, Furness A, Litchfield K, et al.Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies[J]. Cancer Cell, 2018, 33(4):649-663.e4.DOI:10.1016/j.ccell.2018.02.010. [6] Peggs KS, Quezada SA, Chambers CA, et al.Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies[J]. J Exp Med, 2009, 206(8):1717-1725.DOI:10.1084/jem.20082492. [7] Du X, Tang F, Liu M, et al.A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy[J]. Cell Res, 2018, 28(4):416-432.DOI:10.1038/s41422-018-0011-0. [8] Rodriguez-Ruiz ME, Vitale I, Harrington KJ, et al.Immunological impact of cell death signaling driven by radiation on the tumor microenvironment[J]. Nat Immunol, 2020, 21(2):120-134.DOI:10.1038/s41590-019-0561-4. [9] Demaria S, Golden EB, Formenti SC.Role of local radiation therapy in Cancer Immunotherapy[J]. JAMA Oncol, 2015, 1(9):1325-1332.DOI:10.1001/jamaoncol.2015.2756. [10] Jain RK.Normalizing tumor microenvironment to treat cancer:bench to bedside to biomarkers[J]. J Clin Oncol, 2013, 31(17):2205-2218.DOI:10.1200/JCO.2012.46.3653. [11] Hodge JW, Ardiani A, Farsaci B, et al.The tipping point for combination therapy:cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors[J]. Semin Oncol, 2012, 39(3):323-339.DOI:10.1053/j.seminoncol.2012.02.006. [12] Muroyama Y, Nirschl TR, Kochel CM, et al.Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment[J]. Cancer Immunol Res, 2017, 5(11):992-1004.DOI:10.1158/2326-6066.CIR-17-0040. [13] Qin R, Olson A, Singh B, et al.Safety and efficacy of radiation therapy in advanced melanoma patients treated with ipilimumab[J]. Int J Radiat Oncol Biol Phys, 2016, 96(1):72-77.DOI:10.1016/j.ijrobp.2016.04.017. [14] Nickols NG, Lin L, Kane N, et al.High dose per fraction radiation therapy increases both tumor-infiltrating lymphocytes and suppressive immune cells in prostate cancer[J]. Int J Radiat Oncol Biol Phys, 2018, 102(3):S203-S204.DOI:10.1016/j.ijrobp.2018.07.107. [15] Persa E, Balogh A, Sáfrány G, et al.The effect of ionizing radiation on regulatory T cells in health and disease[J]. Cancer Lett, 2015, 368(2):252-261.DOI:10.1016/j.canlet.2015.03.003. [16] Liu C, Sun B, Hu X, et al.Stereotactic ablative radiation therapy for pulmonary recurrence-based oligometastatic non-small cell lung cancer:survival and prognostic value of regulatory T cells[J]. Int J Radiat Oncol Biol Phys, 2019, 105(5):1055-1064.DOI:10.1016/j.ijrobp.2019.08.012. [17] Chatzinikolaou G, Karakasilioti I, Garinis GA.DNA damage and innate immunity:links and trade-offs[J]. Trends Immunol, 2014, 35(9):429-435.DOI:10.1016/j.it.2014.06.003. [18] Kulzer L, Rubner Y, Deloch L, et al.Norm-and hypo-fractionated radiotherapy is capable of activating human dendritic cells[J]. J Immunotoxicol, 2014, 11(4):328-336.DOI:10.3109/1547691X.2014.880533. [19] Rudqvist NP, Pilones KA, Lhuillier C, et al.Radiotherapy and CTLA-4 blockade shape the TCR repertoire of tumor-infiltrating T cells[J]. Cancer Immunol Res, 2018, 6(2):139-150.DOI:10.1158/2326-6066.CIR-17-0134. [20] 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. [21] 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. [22] 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. [23] Grimaldi AM, Simeone E, Giannarelli D, et al.Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy[J]. Oncoimmunology, 2014, 3:e28780.DOI:10.4161/onci.28780. [24] Silk AW, Bassetti MF, West BT, et al.Ipilimumab and radiation therapy for melanoma brain metastases[J]. Cancer Med, 2013, 2(6):899-906.DOI:10.1002/cam4.140. [25] Sundahl N, De Wolf K, Kruse V, et al.Phase 1 dose escalation trial of ipilimumab and stereotactic body radiation therapy in metastatic melanoma[J]. Int J Radiat Oncol Biol Phys, 2018, 100(4):906-915.DOI:10.1016/j.ijrobp.2017.11.029. [26] Welsh JW, Tang C, de Groot P, et al.Phase Ⅱ trial of ipilimumab with stereotactic radiation therapy for metastatic disease:outcomes, toxicities, and low-dose radiation-related abscopal responses[J]. Cancer Immunol Res, 2019, 7(12):1903-1909.DOI:10.1158/2326-6066.CIR-18-0793. [27] Formenti SC, Rudqvist NP, Golden E, et al.Radiotherapy induces responses of lung cancer to CTLA-4 blockade[J]. Nat Med, 2018, 24(12):1845-1851.DOI:10.1038/s41591-018-0232-2. [28] 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[J/OL]. PLoS One, 2014, 9(3):e92572.DOI:10.1371/journal.pone.0092572. [29] Young KH, Baird JR, Savage T, et al.Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy[J]. PLoS One, 2016, 11(6):e0157164.DOI:10.1371/journal.pone.0157164. [30] 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. [31] Schmidberger H, Rapp M, Ebersberger A, et al.Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma:sequence matters[J]. Strahlenther Onkol, 2018, 194(12):1144-1151.DOI:10.1007/s00066-018-1356-5. [32] Sodji Q, Gutkin PM, Hiniker SM, et al.Durability of abscopal effect in metastatic melanoma patients after the combination of radiation therapy and ipilimumab:update on a prospective clinical trial[J]. Int J Radiat Oncol Biol Phys, 2019, 105(1):S61-S62.DOI:10.1016/j.ijrobp.2019.06.503. [33] Welsh JW, Tang C, Groot PD, et al.Phase 2 5-arm trial of ipilimumab plus lung or liver stereotactic radiation for patients with advanced malignancies[J]. Int J Radiat Oncol Biol Phys, 2017, 99(5):1315.DOI:10.1016/j.ijrobp.2017.09.012. [34] Ratnayake G, Reinwald S, Shackleton M, et al.Stereotactic radiotherapy combined with immunotherapy is safe and effective:results from a phase I clinical trial[J]. Int J Radiat Oncol Biol Phys, 2019, 105(1):S61.DOI:10.1016/j.ijrobp.2019.06.502. [35] Ratnayake G, Reinwald S, Shackleton MJ, et al.Stereotactic radiotherapy combined with immunotherapy is safe and effective:results from a phase I clinical trial[J]. J Clin Oncol, 2019, 37(15 suppl):9557.DOI:10.1200/JCO.2019.37.15_suppl.9557. [36] 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[J]. Clin Cancer Res, 2017, 23(6):1388-1396.DOI:10.1158/1078-0432.CCR-16-1432.
2021, Vol. 30 
