Title: Recurrent or primary metastatic cervical cancer: current and future treatments
Abstract: •The majority of recurrent or metastatic CCs are considered incurable disease.•Combination of chemotherapy with bevacizumab and pembrolizumab (PD-L1 CPS ≥1) is the new standard of care in first line.•Tisotumab vedotin, an antibody–drug conjugate targeting the tissue factor, is another emerging drug.•Need for more potent biomarkers to accurately determine which patients would receive the greatest benefit from these drugs. Despite screening programs for early detection and the approval of human papillomavirus vaccines, around 6% of women with cervical cancer (CC) are discovered with primary metastatic disease. Moreover, one-third of the patients receiving chemoradiation followed by brachytherapy for locally advanced disease will have a recurrence. At the end, the vast majority of recurrent or metastatic CC not amenable to locoregional treatments are considered incurable disease with very poor prognosis. Historically, cisplatin monotherapy, then a combination of cisplatin and paclitaxel were considered the standard of care. Ten years ago, the addition of bevacizumab to chemotherapy demonstrated favorable data in terms of response rate and overall survival. Even with this improvement, novel therapies are needed for the treatment of recurrent CC in first as well as later lines. In the last decades, a better understanding of the interactions between human papillomavirus infection and the host immune system response has focused interest on the use of immunotherapeutic drugs in CC patients. Indeed, immune checkpoint inhibitors (pembrolizumab, cemiplimab, and others) have recently emerged as novel therapeutic pillars that could provide durable responses with impact on overall survival in patients in the primary (in addition to chemotherapy) or recurrent (monotherapy) settings. Tisotumab vedotin, an antibody–drug conjugate targeting the tissue factor, is another emerging drug. Several trials in monotherapy or in combination with immunotherapy, chemotherapy, or bevacizumab showed very promising results. There is a high need for more potent biomarkers to better accurately determine which patients would receive the greatest benefit from all these aforementioned drugs, but also to identify patients with specific molecular characteristics that could benefit from other targeted therapies. The Cancer Genome Atlas Research Network identified several genes significantly mutated, potentially targetable. These molecular data have highlighted the molecular heterogeneity of CC. Despite screening programs for early detection and the approval of human papillomavirus vaccines, around 6% of women with cervical cancer (CC) are discovered with primary metastatic disease. Moreover, one-third of the patients receiving chemoradiation followed by brachytherapy for locally advanced disease will have a recurrence. At the end, the vast majority of recurrent or metastatic CC not amenable to locoregional treatments are considered incurable disease with very poor prognosis. Historically, cisplatin monotherapy, then a combination of cisplatin and paclitaxel were considered the standard of care. Ten years ago, the addition of bevacizumab to chemotherapy demonstrated favorable data in terms of response rate and overall survival. Even with this improvement, novel therapies are needed for the treatment of recurrent CC in first as well as later lines. In the last decades, a better understanding of the interactions between human papillomavirus infection and the host immune system response has focused interest on the use of immunotherapeutic drugs in CC patients. Indeed, immune checkpoint inhibitors (pembrolizumab, cemiplimab, and others) have recently emerged as novel therapeutic pillars that could provide durable responses with impact on overall survival in patients in the primary (in addition to chemotherapy) or recurrent (monotherapy) settings. Tisotumab vedotin, an antibody–drug conjugate targeting the tissue factor, is another emerging drug. Several trials in monotherapy or in combination with immunotherapy, chemotherapy, or bevacizumab showed very promising results. There is a high need for more potent biomarkers to better accurately determine which patients would receive the greatest benefit from all these aforementioned drugs, but also to identify patients with specific molecular characteristics that could benefit from other targeted therapies. The Cancer Genome Atlas Research Network identified several genes significantly mutated, potentially targetable. These molecular data have highlighted the molecular heterogeneity of CC. IntroductionAccording to GLOBOCAN 2020, cervical cancer (CC) is the fourth most common cancer in women worldwide after breast, colorectal, and lung cancers, respectively, and is the second most common cancer in developing countries, where >85% of cases occur. Worldwide, an estimated 604 000 new cases of CC and 342 000 deaths are recorded, although incidence and mortality vary widely among countries.1Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (19800) Google Scholar,2Arbyn M. Weiderpass E. Bruni L. et al.Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis.Lancet Glob Health. 2020; 8: e191-e203Abstract Full Text Full Text PDF PubMed Scopus (1305) Google Scholar In developed countries, incidence has decreased over the past 30 years due to the introduction of screening and vaccination programs.3Cohen P.A. Jhingran A. Oaknin A. Denny L. Cervical cancer.Lancet. 2019; 393: 169-182Abstract Full Text Full Text PDF PubMed Scopus (822) Google ScholarA persistent infection with human papillomavirus (HPV), a sexually transmitted deoxyribonucleic acid (DNA) virus, is detected in 99% of CC cases. Although the majority of HPV infections are transitory, HPV persists in 10% of cases, leading to the development of a preinvasive or invasive lesion 15-20 years after the initial infection.4Hebner C.M. Laimins L.A. Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity.Rev Med Virol. 2006; 16: 83-97Crossref PubMed Scopus (256) Google ScholarHPVs encode two oncoproteins, E6 and E7, which play critical roles in the development of HPV-induced carcinogenesis.The E6 protein induces principally p53 degradation and the up-regulation of vascular endothelial growth factor (VEGF) which, in turn, lead to angiogenesis. E7 inactivates the retinoblastoma protein (pRb), increasing Ki-67 protein levels. Both E6 and E7 proteins also induce AKT phosphorylation that causes cell survival and proliferation; but they also activate transcription factors inducing cellular invasion.5Barillari G. Monini P. Sgadari C. Ensoli B. The impact of Human Papilloma Viruses, matrix metallo-proteinases and HIV protease inhibitors on the onset and progression of uterine cervix epithelial tumors: a review of preclinical and clinical studies.Int J Mol Sci. 2018; 19: 1418Crossref Scopus (11) Google ScholarSquamous cell carcinoma (SCC), adenocarcinoma (ADK), and adenosquamous carcinoma (ADSC) are the three most common histological subtypes, accounting for 70%, 25%, and 5% of cases, respectively. In contrast to SCC which has experienced a progressive decrease in incidence and mortality in recent decades, the incidence and mortality of ADK has increased during the same timeframe.6Adegoke O. Kulasingam S. Virnig B. Cervical cancer trends in the United States: a 35-year population-based analysis.J Womens Health (Larchmt). 2012; 21: 1031-1037Crossref PubMed Scopus (193) Google Scholar This evolution has been attributed to the Papanicolaou test and its ability to detect squamous, rather than glandular, neoplasia more efficiently.7Zappa M. Visioli C.B. Ciatto S. Iossa A. Paci E. Sasieni P. Lower protection of cytological screening for adenocarcinomas and shorter protection for younger women: the results of a case-control study in Florence.Br J Cancer. 2004; 90: 1784-1786Crossref PubMed Google ScholarOverall survival (OS) at 5 years is approximately 92%, 65%, and 17% for early-stage, locally advanced, and metastatic disease, respectively. The prognosis of patients with recurrent disease remains very poor, with an estimated OS around 13-17 months.8Cibula D. Pötter R. Planchamp F. et al.The European Society of Gynaecological Oncology/European Society for radiotherapy and oncology/European society of pathology guidelines for the management of patients with cervical cancer.Int J Gynecol Cancer. 2018; 28: 641-655Crossref PubMed Scopus (226) Google Scholar Even with the major progresses made and the optimized treatment of locally advanced CC (LACC) over the past two decades, around 30% of patients will suffer from recurrent disease.9Gennigens C. De Cuypere M. Hermesse J. Kridelka F. Jerusalem G. Optimal treatment in locally advanced cervical cancer.Expert Rev Anticancer Ther. 2021; 21: 657-671Crossref PubMed Scopus (7) Google Scholar Moreover, around 6% of the women are discovered with primary metastatic disease. By a majority, patients in recurrence will benefit from systemic treatments such as chemotherapy (CT) with or without angiogenesis inhibitors. Surgery (exenteration) is an option for only a very well selected group of patients.10Sardain H. Lavoue V. Redpath M. Bertheuil N. Foucher F. Levêque J. Curative pelvic exenteration for recurrent cervical carcinoma in the era of concurrent chemotherapy and radiation therapy. A systematic review.Eur J Surg Oncol. 2015; 41: 975-985Abstract Full Text Full Text PDF PubMed Google ScholarIn this review, we discuss historical, current, and emerging treatment options for patients with primary metastatic or recurrent CC.ChemotherapyCisplatin monotherapyHistorically, disseminated recurrent CC was treated with cisplatin monotherapy that was considered as the standard of care (SOC) since the results of the phase II Gynecologic Oncology Group (GOG)-26 trial. Most of the patients included were chemonaive as radiotherapy (RT) alone was the established treatment of LACC patients at that time. The overall response rate (ORR) and the median OS (mOS) were 38% and 9 months, respectively.11Thigpen T. Shingleton H. Homesley H. Lagasse L. Blessing J. Cis-platinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group.Cancer. 1981; 48: 899-903Crossref PubMed Scopus (271) Google Scholar Another GOG trial demonstrated that the 100 mg/m2 single-dose schedule has produced a statistically higher ORR than the 50 mg/m2 regimen, without impact on survival, but with higher toxicity.12Bonomi P. Blessing J.A. Stehman F.B. DiSaia P.J. Walton L. Major F.J. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study.J Clin Oncol. 1985; 3: 1079-1085Crossref PubMed Scopus (375) Google ScholarNon-cisplatin agentsSeveral non-platinum drugs were also tested in phase II trials such as paclitaxel, irinotecan, topotecan, vinorelbine, ifosfamide, but also 5-fluorouracil, docetaxel, doxorubicin, gemcitabine, and mitomycin. An ORR of 15%-46% was observed but with median progression-free survival (mPFS) around 2-3 months and limited gains in OS.13Tsuda N. Watari H. Ushijima K. Chemotherapy and molecular targeting therapy for recurrent cervical cancer.Chin J Cancer Res. 2016; 28: 241-253Crossref PubMed Scopus (34) Google ScholarCisplatin ‘doublet’ combinationsSeveral trials were conducted with cisplatin plus ifosfamide, gemcitabine, topotecan (GOG-179), paclitaxel (GOG-169), or vinorelbine. All these combinations increased PFS but only the combination of topotecan with cisplatin statistically increased the mOS. The GOG-179 trial was conducted in parallel with the approval of cisplatin as radiosensitizing agent in locally advanced setting. Therefore, 40% of patients had not received prior cisplatin and the effect of the combination schedule was less beneficial in the population receiving chemoradiation, despite remaining statistically significant.14Long 3rd, H.J. Bundy B.N. Grendys E.C. et al.Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study.J Clin Oncol. 2005; 23: 4626-4633Crossref PubMed Scopus (462) Google Scholar In the light of these studies, the GOG-204 evaluated four platinum doublets consisting of cisplatin with paclitaxel, gemcitabine, topotecan, or vinorelbine. The first doublet demonstrated an ORR, PFS, and OS of 29.1%, 5.8, and 12.9 months, respectively. No statistical superiority between arms was demonstrated despite there was a trend in all the endpoints favoring paclitaxel with cisplatin. Nevertheless, this combination was considered the SOC, especially in women who had not received prior cisplatin-based therapy.15Monk B.J. Sill M.W. McMeekin D.S. et al.Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study.J Clin Oncol. 2009; 27: 4649-4655Crossref PubMed Scopus (483) Google Scholar,16Moore D.H. Blessing J.A. McQuellon R.P. et al.Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study.J Clin Oncol. 2004; 22: 3113-3119Crossref PubMed Scopus (490) Google ScholarCisplatin ‘triplet’ combinationsIn the GOG-179 trial, there was also a third comparison arm using the combination of methotrexate with vinblastine, adriamycin, and cisplatin (MVAC) regimen, but that arm was stopped early due to a higher rate of treatment-related deaths.14Long 3rd, H.J. Bundy B.N. Grendys E.C. et al.Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study.J Clin Oncol. 2005; 23: 4626-4633Crossref PubMed Scopus (462) Google Scholar Two phase II trials confirmed that other triplet regimens did not improve outcome but increased toxicity.17Zanetta G. Fei F. Parma G. et al.Paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy for recurrent or persistent squamous-cell cervical cancer.Ann Oncol. 1999; 10: 1171-1174Abstract Full Text PDF PubMed Scopus (45) Google Scholar,18Bloss J.D. Blessing J.A. Behrens B.C. et al.Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a gynecologic oncology group study.J Clin Oncol. 2002; 20: 1832-1837Crossref PubMed Scopus (117) Google ScholarCarboplatinThe JCOG-0505 non-inferior study randomized 253 patients with stage IVB recurrent CC between paclitaxel and carboplatin or cisplatin. Paclitaxel plus carboplatin demonstrated its non-inferiority regarding PFS and OS, and its significant reduction in toxicity. Nevertheless, a post hoc analysis revealed that the cisplatin doublet regimen was superior in the subgroup of patients who had not received prior cisplatin.19Kitagawa R. Katsumata N. Shibata T. et al.Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: The open-label randomized phase III trial JCOG0505.J Clin Oncol. 2015; 33: 2129-2135Crossref PubMed Scopus (232) Google ScholarAngiogenesis inhibitorsRationaleTumor foci relapsing or persisting in the irradiated field may have compromised the blood supply, inducing hypoxia and therefore limiting the delivery of CT drugs. These characteristics may explain the limited response to retreatment with traditional CT. Moreover, we have previously described the effects of E6/E7 proteins on the angiogenic pathway.5Barillari G. Monini P. Sgadari C. Ensoli B. The impact of Human Papilloma Viruses, matrix metallo-proteinases and HIV protease inhibitors on the onset and progression of uterine cervix epithelial tumors: a review of preclinical and clinical studies.Int J Mol Sci. 2018; 19: 1418Crossref Scopus (11) Google Scholar Furthermore, VEGF has been identified as a major pro-angiogenic factor and marker of poor prognosis. In fact, overexpression of VEGF/VEGF correlates with larger tumors, parametrial infiltration, lymph node involvement, distant metastasis, and poorer OS; and was also observed in tumor samples obtained from CC patients with post-RT relapse.20Eskander R.N. Tewari K.S. Development of bevacizumab in advanced cervical cancer: pharmacodynamic modeling, survival impact and toxicology.Future Oncol. 2015; 11: 909-922Crossref PubMed Scopus (11) Google Scholar, 21Cheng W.F. Chen C.A. Lee C.N. Wei L.H. Hsieh F.J. Hsieh C.Y. Vascular endothelial growth factor and prognosis of cervical carcinoma.Obstet Gynecol. 2000; 96: 721-726Crossref PubMed Scopus (0) Google Scholar, 22Gaffney D.K. Haslam D. Tsodikov A. et al.Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) negatively affect overall survival in carcinoma of the cervix treated with radiotherapy.Int J Radiat Oncol Biol Phys. 2003; 56: 922-928Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 23Ceci C. Atzori M.G. Lacal P.M. Graziani G. Role of VEGFs/VEGFR-1 signaling and its inhibition in modulating tumor invasion: experimental evidence in different metastatic cancer models.Int J Mol Sci. 2020; 21: E1388Crossref PubMed Scopus (75) Google ScholarBevacizumabBevacizumab, a humanized monoclonal antibody targeting VEGF, was the most widely studied and used anti-angiogenic therapy in patients with CC.24Minion L.E. Tewari K.S. Cervical cancer-state of the science: from angiogenesis blockade to checkpoint inhibition.Gynecol Oncol. 2018; 148: 609-621Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Based on the favorable results in a phase II trial (GOG-227C) with heavily pretreated patients, GOG-240, a randomized phase III trial combining bevacizumab with CT (paclitaxel and cisplatin or topotecan) was started. The author demonstrated an improvement in both PFS [8.2 versus 5.9 months; hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.54-0.82] and OS (17.0 versus 13.3 months; HR 0.71, 95% CI 0.54-0.95).25Tewari K.S. Sill M.W. Long 3rd, H.J. et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (911) Google Scholar,26Tewari K.S. Sill M.W. Penson R.T. et al.Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).Lancet. 2017; 390: 1654-1663Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar The Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved these combinations for patients with metastatic, persistent, or recurrent CC in 2014 and 2015, respectively.Other anti-angiogenic drugsOther anti-angiogenic drugs (such as pazopanib, cediranib, apatinib, sunitinib) have been studied alone or in combination with CT. These studies demonstrated some significant benefits but with the addition of toxicities.27Monk B.J. Mas Lopez L. Zarba J.J. et al.Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer.J Clin Oncol. 2010; 28: 3562-3569Crossref PubMed Scopus (206) Google Scholar, 28Symonds R.P. Gourley C. Davidson S. et al.Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Oncol. 2015; 16: 1515-1524Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 29Mackay H.J. Tinker A. Winquist E. et al.A phase II study of sunitinib in patients with locally advanced or metastatic cervical carcinoma: NCIC CTG Trial IND.184.Gynecol Oncol. 2010; 116: 163-167Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 30Vergote I. Van Nieuwenhuysen E. Casado A. et al.199 randomised phase II BGOG/ENGOT-cx1 study of paclitaxel-carboplatin with or without nintedanib in first-line recurrent or advanced cervical cancer.Int J Gynecol Cancer. 2021; 31: A12PubMed Google Scholar The results of the randomized phase II study including 120 patients with primary advanced (25%) or first-line recurrent (75%) CC treated by carboplatin and paclitaxel with or without nintedanib were recently presented by Vergote et al.30Vergote I. Van Nieuwenhuysen E. Casado A. et al.199 randomised phase II BGOG/ENGOT-cx1 study of paclitaxel-carboplatin with or without nintedanib in first-line recurrent or advanced cervical cancer.Int J Gynecol Cancer. 2021; 31: A12PubMed Google Scholar The majority (62%) of the patients had SCC histology and 64% received prior RT. The primary endpoint was met with a PFS at 18 months of 15.1% versus 12.8% in favor of the nintedanib arm (p minuscule = 0.057). Nevertheless, subgroup analysis demonstrated a statistical difference in PFS only in the recurrent setting: the 1-year PFS was 22.8% and 14.9% in favor of nintedanib. The mOS was 21.7 and 16.4 months for nintedanib and control arms, respectively. No new safety signals were observed.30Vergote I. Van Nieuwenhuysen E. Casado A. et al.199 randomised phase II BGOG/ENGOT-cx1 study of paclitaxel-carboplatin with or without nintedanib in first-line recurrent or advanced cervical cancer.Int J Gynecol Cancer. 2021; 31: A12PubMed Google ScholarEpidermal growth factor receptor inhibitorsEpidermal growth factor receptor (EGFR) overexpression is demonstrated in 80% of newly diagnosed CC and associated with reduced survival and poor response to chemoradiation.31Tian W.J. Huang M.L. Qin Q.F. Chen Q. Fang K. Wang P.L. Prognostic impact of epidermal growth factor receptor overexpression in patients with cervical cancer: a meta-analysis.PLoS One. 2016; 11e0158787Crossref Scopus (24) Google Scholar, 32Noordhuis M.G. Eijsink J.J.H. Ten Hoor K.A. et al.Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer.Clin Cancer Res. 2009; 15: 7389-7397Crossref PubMed Scopus (90) Google Scholar, 33Kersemaekers A.M. Fleuren G.J. Kenter G.G. et al.Oncogene alterations in carcinomas of the uterine cervix: overexpression of the epidermal growth factor receptor is associated with poor prognosis.Clin Cancer Res. 1999; 5: 577-586PubMed Google Scholar Furthermore, human EGFR2 (HER2) mutations and amplifications were observed in 3%-6% and 1%-12% of CC, respectively, and were also correlated with a worse prognosis.34Itkin B. Garcia A. Straminsky S. et al.Prevalence of HER2 overexpression and amplification in cervical cancer: a systematic review and meta-analysis.PLoS One. 2021; 16e0257976Crossref PubMed Scopus (2) Google Scholar Although EGFR inhibition seemed a promising target in CC treatment, several phase II studies evaluating EGFR inhibitors such as cetuximab, gefitinib, erlotinib, or lapatinib showed only limited activity.27Monk B.J. Mas Lopez L. Zarba J.J. et al.Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer.J Clin Oncol. 2010; 28: 3562-3569Crossref PubMed Scopus (206) Google Scholar,35Santin A.D. Sill M.W. McMeekin D.S. et al.Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.Gynecol Oncol. 2011; 122: 495-500Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 36Goncalves A. Fabbro M. Lhommé C. et al.A phase II trial to evaluate gefitinib as second- or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer.Gynecol Oncol. 2008; 108: 42-46Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 37Schilder R.J. Sill M.W. Lee Y.C. Mannel R. A phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study.Int J Gynecol Cancer. 2009; 19: 929-933Crossref PubMed Scopus (91) Google Scholar Neratinib was explored in the phase II SUMMIT trial including 16 patients (62.5% of ADK) with HER2-mutated recurrent CC progressing after platinum-based treatment. An ORR, mPFS, and mOS of 25%, 7.0, and 16.8 months, respectively, were observed.38Oaknin A. Friedman C.F. Roman L.D. et al.Neratinib in patients with HER2-mutant, metastatic cervical cancer: findings from the phase 2 SUMMIT basket trial.Gynecol Oncol. 2020; 159: 150-156Abstract Full Text Full Text PDF PubMed Scopus (15) Google ScholarImmunotherapyIn the last decades, a better understanding of the interactions between HPV infection and the host immune system response has focused interest on the use of immunotherapeutic drugs in CC patients.RationaleFirstly, almost all cases of CC are driven by high-risk HPV infection. HPV has several mechanisms by which it induces an immunosuppressive tumor microenvironment (TME) and a deficient immunosurveillance. Of particular importance, E6 and E7 proteins modify the expression of transforming growth factor-β (TGF-β) in infected cells. Up-regulation of TGF-β induces an immunosuppressive TME by acting notably on regulatory T (Treg) cells. Furthermore, interleukin 10 (IL-10) changes the cytokine profile from a T helper 1 (Th1) profile to a Th2 profile, which is more immunosuppressive.39Wakabayashi R. Nakahama Y. Nguyen V. Espinoza J.L. The host-microbe interplay in human papillomavirus-induced carcinogenesis.Microorganisms. 2019; 7: E199Crossref PubMed Scopus (24) Google Scholar Secondly, various immune inhibitory molecules such as Programmed cell death-1 (PD-1)/Programmed cell death ligand-1 (PD-L1) are expressed by CC. PD-L1 is rarely observed in normal cervical tissue. PD-L1 expression in SCC varies widely from 19% to 88% according to different series and is less frequent in ADK histology (14%).40Mezache L. Paniccia B. Nyinawabera A. Nuovo G.J. Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers.Mod Pathol. 2015; 28: 1594-1602Crossref PubMed Scopus (165) Google Scholar,41Heeren A.M. Punt S. Bleeker M.C. et al.Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix.Mod Pathol. 2016; 29: 753-763Crossref PubMed Google Scholar Several studies have also demonstrated high expression levels of other immunomodulatory molecules such as cytokines (TGF-β, IL-10), cytotoxic T-lymphocyte antigen-4 (CTLA-4) and surface receptors (TIM3).42Cao Y. Zhou X. Huang X. et al.Tim-3 expression in cervical cancer promotes tumor metastasis.PLoS One. 2013; 8e53834Crossref Scopus (99) Google Scholar,43Kosmaczewska A. Bocko D. Ciszak L. et al.Dysregulated expression of both the costimulatory CD28 and inhibitory CTLA-4 molecules in PB T cells of advanced cervical cancer patients suggests systemic immunosuppression related to disease progression.Pathol Oncol Res. 2012; 18: 479-489Crossref PubMed Scopus (26) Google Scholar Thirdly, the composition of the TME in CC has an impact on survival: CD8+, CD4+, and Treg cells are more abundant in CC than in normal cervical tissue, with a negative impact on survival.44Piersma S.J. Jordanova E.S. van Poelgeest M.I.E. et al.High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer.Cancer Res. 2007; 67: 354-361Crossref PubMed Scopus (311) Google Scholar,45Shah W. Yan X. Jing L. Zhou Y. Chen H. Wang Y. A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4(+)FOXP3(+) regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix.Cell Mol Immunol. 2011; 8: 59-66Crossref PubMed Scopus (164) Google Scholar Finally, CC has an increased total mutational burden (TMB) rate (around 5-6 mutations per megabase).46Alexandrov L.B. Nik-Zainal S. Wedge D.C. et al.Signatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (6107) Google Scholar,47Chalmers Z.R. Connelly C.F. Fabrizio D. et al.Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.Genome Med. 2017; 9: 34Crossref PubMed Scopus (1695) Google ScholarImmune checkpoint inhibitors (ICIs)Inhibitors of PD-1 (pembrolizumab, nivolumab, cemiplimab, balstilimab) and PD-L1 (atezolizumab, avelumab, durvalumab, camrelizumab), as well as inhibitors of CTLA-4 (ipilimumab, zalifrelimab) are being evaluated in several CC trials48Cohen A.C. Roane B.M. Leath C.A. Novel therapeutics for recurrent cervical cancer: moving towards personalized therapy.Drugs. 2020; 80: 217-227Crossref PubMed Scopus (32) Google Scholar,49Kagabu M. Nagasawa T. Sato C. et al.Immunotherapy for uterine cervical cancer using checkpoint inhibitors: future directions.Int J Mol Sci. 2020; 21: E2335Crossref PubMed Scopus (27) Google Scholar (see Table 1, Table 2, Table 3, Table 4). Table 1 summarizes the results of monotherapy clinical trials.Table 1Monotherapy clinical trialsDrugTrialPhaseNPopulationHistology (%)Prior RT (%)Prior bevacizumab (%)PD-L1 expression (%)Number of prior lines (%)ORR (%)mDOR (months)mPFS (months)mOS (months)Grade 3-4 TRAEs (%)Discontinuation (%)PembrolizumabKEYNOTE-028Ib24Locally advanced or metastatic; PD-L1+; progression after prior therapySCC = 96ADK = 49242TC = 75TC + stroma = 251 = 382 = 25≥3 = 38175.421120.88.3KEYNOTE-158II98Advanced disease; progression during or intolerance to ≥1 lines of prior therapySCC = 93.9ADK = 5.1ADSC = 1.086.741.8CPS ≥1 = 83.71 = 30.62 = 34.7≥3 = 30.6All = 12.2PD-L1+ = 14.6PD-L1− = 0NR2.19.412.24.1NivolumabCheckMate-358I/II19Recurrent or metastatic; HPV+; SCCSCC = 10089.531.6CPS ≥1 = 62.51 = 42.12 = 42.13 = 15.826.3NR5.121.921.15.3NRG-GY002