The authors wish to acknowledge Dr. Arta Monjazeb for his contribution in generating Figure 1.
Disclosures: Dr. Zamarin has disclosed that he served as the Co-Chair of the Cervical Cancer Translational Research Team at NRG Oncology, and is a consultant for and has a patent license with Merck. Dr. Mayadev has disclosed that she serves as the Co-Chair of the Cervix/Vulva Cancer Subcommittee at NRG Oncology, is a consultant for AstraZeneca, and serves on the GOG Foundation Advisory Board for ad-hoc clinical trial meetings. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
See JNCCN.org for supplemental online content.
Hreshchyshyn MM, Aron BS, Boronow RC et al.. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys 1979;5:317–322.
Keys HM, Bundy BN, Stehman FB et al.. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–1161.
Morris M, Eifel PJ, Lu J et al.. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137–1143.
Rose PG, Bundy BN, Watkins EB et al.. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153.
Stehman FB, Ali S, Keys HM et al.. Radiation therapy with or without weekly cisplatin for bulky stage 1B cervical carcinoma: follow-up of a Gynecologic Oncology Group trial. Am J Obstet Gynecol 2007;197:503. e1–6.
Vale CL, Tierney JF, Davidson SE et al.. Substantial improvement in UK cervical cancer survival with chemoradiotherapy: results of a Royal College of Radiologists' audit. Clin Oncol (R Coll Radiol) 2010;22:590–601.
Varia MA, Bundy BN, Deppe G et al.. Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 1998;42:1015–1023.
Randall LM, Monk BJ, Darcy KM et al.. Markers of angiogenesis in high-risk, early-stage cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2009;112:583–589.
Tewari KS, Sill MW, Long HJ III et al.. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;70:734–743.
Chung HC, Schellens JH, Delord JP et al.. Pembrolizumab treatment of advanced cervical cancer: updated results from the phase 2 KEYNOTE-158 study [abstract]. J Clin Oncol 2018;32(Suppl):Abstract 5522.
Stevanovic S, Draper LM, Langhan MM et al.. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol 2015;33:1543–1550.
Clifford GM, Smith JS, Plummer M et al.. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003;88:63–73.
Munoz N, Bosch FX, de Sanjose S et al.. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518–527.
Eskander RN, Tewari KS. Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer. Clin Ther 2015;37:20–38.
Mueller N. Overview of the epidemiology of malignancy in immune deficiency. J Acquir Immune Defic Syndr 1999;21(Suppl 1):S5–10.
Su TH, Chang TY, Lee YJ et al.. CTLA-4 gene and susceptibility to human papillomavirus-16-associated cervical squamous cell carcinoma in Taiwanese women. Carcinogenesis 2007;28:1237–1240.
Kazemi T, Younesi V, Jadidi-Niaragh F, Yousefi M. Immunotherapeutic approaches for cancer therapy: an updated review. Artif Cells Nanomed Biotechnol 2016;44:769–779.
Romano E, Kusio-Kobialka M, Foukas PG et al.. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by non-classical monocytes in melanoma patients. Proc Natl Acad Sci U S A 2015;112:6140–6145.
Butte MJ, Keir ME, Phamduy TB et al.. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007;27:111–122.
Tsushima F, Yao S, Shin T et al.. Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood 2007;110:180–185.
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012;24:207–212.
Ghebeh H, Mohammed S, Al-Omair A et al.. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia 2006;8:190–198.
Hamanishi J, Mandai M, Iwasaki M et al.. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 2007;104:3360–3365.
Thompson RH, Kuntz SM, Leibovich BC et al.. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 2006;66:3381–3385.
Wu C, Zhu Y, Jiang J et al.. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 2006;108:19–24.
Ohigashi Y, Sho M, Yamada Y et al.. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 2005;11:2947–2953.
Akbari O, Stock P, Singh AK et al.. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunol 2010;3:81–91.
Karim R, Jordanova ES, Piersma SJ et al.. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res 2009;15:6341–6347.
Heeren AM, Punt S, Bleeker MC et al.. Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix. Mod Pathol 2016;29:753–763.
Chen Z, Pang N, Du R et al.. Elevated expression of programmed death-1 and programmed death ligand-1 negatively regulates immune response against cervical cancer cells. Mediators Inflamm 2016;2016:6891482.
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.
Levy A, Chargari C, Cheminant M et al.. Radiation therapy and immunotherapy: implications for a combined cancer treatment. Crit Rev Oncol Hematol 2013;85:278–287.
Hallahan D, Kuchibhotla J, Wyble C. Cell adhesion molecules mediate radiation-induced leukocyte adhesion to the vascular endothelium. Cancer Res 1996;56:5150–5155.
Sharabi AB, Lim M, DeWeese TL et al.. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 2015;16:e498–509.
Chung TD, Mauceri HJ, Hallahan DE et al.. Tumor necrosis factor-alpha-based gene therapy enhances radiation cytotoxicity in human prostate cancer. Cancer Gene Ther 1998;5:344–349.
Mauceri HJ, Hanna NN, Wayne JD et al.. Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature. Cancer Res 1996;56:4311–4314.
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.
Hatfield P, Merrick A, Harrington K et al.. Radiation-induced cell death and dendritic cells: potential for cancer immunotherapy? Clin Oncol (R Coll Radiol) 2005;17:1–11.
Wong P, Houghton P, Kirsch DG et al.. Combining targeted agents with modern radiotherapy in soft tissue sarcomas. J Natl Cancer Inst 2014;106:dju329.
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.
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.
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.
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.
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.
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.
Lheureux S, Butler MO, Clarke B et al.. Association of ipilimumab with safety and antitumor activity in women with metastatic or recurrent human papillomavirus-related cervical carcinoma. JAMA Oncol 2018;4:e173776.
Mayadev J, Brady WE, Lin YG et al.. A phase I study of sequential ipilimumab in the definitive treatment of node positive cervical cancer: GOG 9929 [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 5526.
Adachi K, Tamada K. Immune checkpoint blockade opens an avenue of cancer immunotherapy with a potent clinical efficacy. Cancer Sci 2015;106:945–950.
Chung HC, Schellens JH, Delord JP et al.. Pembrolizumab treatment of advanced cervical cancer: updated results from the phase 2 KEYNOTE-158 study [abstract]. J Clin Oncol 2018;36(Suppl):Abstract 5522.
Frenel JS, Le Tourneau C, O'Neil B et al.. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol 2017;35:4035–4041.
Hollebecque A MT, Moore K et al.. An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers. J Clin Oncol 2017;35(Supp):Abstract 5504.
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. Hollebecque A MT Moore K An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers. J Clin Oncol 2017; 35( Supp): Abstract 5504.
Wallecha A, Carroll KD, Maciag PC et al.. Multiple effector mechanisms induced by recombinant Listeria monocytogenes anticancer immunotherapeutics. Adv Appl Microbiol 2009;66:1–27.
Basu P, Mehta A, Jain M et al.. A randomized phase 2 study of ADXS11-001 Listeria monocytogenes-listeriolysin O immunotherapy with or without cisplatin in treatment of advanced cervical cancer. Int J Gynecol Cancer 2018;28:764–772.
Huh WK, Dizon DS, Powell MA et al.. ADXS11-001 immunotherapy in squamous or non-squamous persistent/recurrent metastatic cervical cancer: results from stage I of the phase II GOG/NRG0265 study [abstract]. J Clin Oncol 2016;34(15 Suppl):Abstract 5516.