The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers

Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell death protein-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anticytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), which have been approved for treating different types of malignancies. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host–tumor interaction. There are several the US food and drug administration (FDA)-approved ICIs targeting PD-1, including pembrolizumab and nivolumab, as well as those targeting PD-L1, including avelumab, atezolizumab, and durvalumab for melanoma, renal cell cancer, colorectal cancer, head and neck cancer, cervix cancer, urothelial cancer, and lung cancer. Current pre-clinical and clinical studies assessing PD-1/PD-L1 inhibitors in several gynecologic cancers have reported significant antitumor activity. In this review, we investigate pre-clinical and clinical studies that describe the safety and efficacy of anti-PD-1/PD-L1 antibodies, with a particular focus on ongoing clinical trials, analyzing the oncological outcome and adverse effects of ICIs in gynecologic cancers.

[1]  B. Baradaran,et al.  Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials , 2020, International journal of molecular sciences.

[2]  R. Burger,et al.  Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study. , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  D. Longo,et al.  Minimal PD-1 expression in mouse and human NK cells under diverse conditions. , 2020, The Journal of clinical investigation.

[4]  P. Rustamadji,et al.  Fas Ligand (FasL) in Association with Tumor-Infiltrating Lymphocytes (TILs) in Early Stage Cervical Cancer , 2020, Asian Pacific journal of cancer prevention : APJCP.

[5]  J. Trovik,et al.  High degree of heterogeneity of PD-L1 and PD-1 from primary to metastatic endometrial cancer. , 2020, Gynecologic oncology.

[6]  A. Jazaeri,et al.  Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002). , 2020, Gynecologic oncology.

[7]  S. Weissman,et al.  An Overview of Advances in Cell-Based Cancer Immunotherapies Based on the Multiple Immune-Cancer Cell Interactions. , 2019, Methods in molecular biology.

[8]  C. Aghajanian,et al.  Anti-PD-L1 (atezolizumab) as an immune primer and concurrently with extended-field chemoradiotherapy for node-positive locally advanced cervical cancer , 2019, International Journal of Gynecological Cancer.

[9]  Pembrolizumab With Axitinib in Recurrent Endometrial Cancer , 2019, Case Medical Research.

[10]  Bin Wu,et al.  Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors , 2019, Front. Oncol..

[11]  P. Sopp,et al.  A Comprehensive Analysis of Key Immune Checkpoint Receptors on Tumor-Infiltrating T Cells From Multiple Types of Cancer , 2019, Front. Oncol..

[12]  A. Oaknin,et al.  A randomized phase III trial of platinum chemotherapy plus paclitaxel with bevacizumab and atezolizumab versus platinum chemotherapy plus paclitaxel and bevacizumab in metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030) , 2019, International Journal of Gynecological Cancer.

[13]  Cesar M. Castro,et al.  Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial. , 2019, JAMA oncology.

[14]  M. Migden,et al.  Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma , 2019, Expert review of clinical pharmacology.

[15]  Z. Tian,et al.  NK Cell Dysfunction and Checkpoint Immunotherapy , 2019, Front. Immunol..

[16]  Yulei N. Wang,et al.  Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers. , 2019, Gynecologic oncology.

[17]  E. Kohn,et al.  A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1–3 inhibitor, cediranib, in recurrent women’s cancers with biomarker analyses , 2019, Journal of Immunotherapy for Cancer.

[18]  T. Fukumoto,et al.  HDAC6 inhibition synergizes with anti-PD-L1 therapy in ARID1A-inactivated ovarian cancer. , 2019, Cancer research.

[19]  F. Bertucci,et al.  PD-1/PD-L1 Targeting in Breast Cancer: The First Clinical Evidences are Emerging—A Literature Review , 2019, Cancers.

[20]  S. Ghai,et al.  Risk Factors of Cervical Cancer: A Case-Control Study , 2019, Asia-Pacific journal of oncology nursing.

[21]  L. Moretta,et al.  PD/1-PD-Ls Checkpoint: Insight on the Potential Role of NK Cells , 2019, Front. Immunol..

[22]  A. Snyder,et al.  A phase II study of atezolizumab in combination with bevacizumab in patients with recurrent, persistent or metastatic cervical cancer , 2019, Gynecologic Oncology.

[23]  A. Mills,et al.  PD-L1 Expression and Tumor-infiltrating Lymphocytes in Uterine Smooth Muscle Tumors: Implications for Immunotherapy , 2019, The American journal of surgical pathology.

[24]  P. V. van Dam,et al.  PRIMMO study protocol: a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer , 2019, BMC Cancer.

[25]  M. Lumsden,et al.  Management of Induced Menopause in Gynaecological Cancers and Their Challenges , 2019, Current Obstetrics and Gynecology Reports.

[26]  E. Schmidt,et al.  Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. , 2019, The Lancet. Oncology.

[27]  D. Campana,et al.  Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells. , 2019, The Journal of clinical investigation.

[28]  Haitao Zhao,et al.  Combination regimens with PD-1/PD-L1 immune checkpoint inhibitors for gastrointestinal malignancies , 2019, Journal of Hematology & Oncology.

[29]  V. Longo,et al.  Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review , 2019, Cancers.

[30]  S. Wong,et al.  Targeting immune cells for cancer therapy , 2019, Redox biology.

[31]  G. Tabellini,et al.  Strengthening the AntiTumor NK Cell Function for the Treatment of Ovarian Cancer , 2019, International journal of molecular sciences.

[32]  Li Wu,et al.  PD-1/PD-L1 Inhibitors in Cervical Cancer , 2019, Front. Pharmacol..

[33]  S. M. Hassanian,et al.  PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[34]  D. Matei,et al.  Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. , 2019, Gynecologic oncology.

[35]  M. Janda,et al.  Challenges and controversies in the conservative management of uterine and ovarian cancer. , 2019, Best practice & research. Clinical obstetrics & gynaecology.

[36]  M. Schiavi,et al.  Immunotherapy in endometrial cancer: new scenarios on the horizon , 2019, Journal of gynecologic oncology.

[37]  Shasha Liu,et al.  Fates of CD8+ T cells in Tumor Microenvironment , 2018, Computational and structural biotechnology journal.

[38]  M. Podhola,et al.  Hepatic Injury Induced by a Single Dose of Nivolumab - a Case Report and Literature Review. , 2019, Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti.

[39]  Melahat Yildirim,et al.  Expression of Immunomodulatory Molecules PD-1, PD-L1, and PD-L2, and their Relationship With Clinicopathologic Characteristics in Endometrial Cancer , 2019, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[40]  B. Lü,et al.  Tumor-infiltrating CD8+ and FOXP3+ lymphocytes before and after neoadjuvant chemotherapy in cervical cancer , 2018, Diagnostic Pathology.

[41]  G. Kenter,et al.  ‘DURVIT’: a phase-I trial of single low-dose durvalumab (Medi4736) IntraTumourally injected in cervical cancer: safety, toxicity and effect on the primary tumour- and lymph node microenvironment , 2018, BMC Cancer.

[42]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[43]  M. McBurney,et al.  Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade , 2018, The Journal of clinical investigation.

[44]  O. Awolude,et al.  Cervical cancer worldwide. , 2018, Current problems in cancer.

[45]  K. Hargadon,et al.  Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. , 2018, International immunopharmacology.

[46]  P. Goodfellow,et al.  Endometrial cancer: Molecular markers and management of advanced stage disease. , 2018, Gynecologic oncology.

[47]  Huyi Liang,et al.  PD-L1 Expression Correlates With Tumor Infiltrating Lymphocytes And Response To Neoadjuvant Chemotherapy In Cervical Cancer , 2018, Journal of Cancer.

[48]  Huan Wang,et al.  Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity , 2018, Nature Immunology.

[49]  B. Zhu,et al.  Potent immunogenicity in BRCA1‐mutated patients with high‐grade serous ovarian carcinoma , 2018, Journal of cellular and molecular medicine.

[50]  F. Giles,et al.  Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC) , 2018, Journal of Immunotherapy for Cancer.

[51]  R. Weinberg,et al.  Understanding the tumor immune microenvironment (TIME) for effective therapy , 2018, Nature Medicine.

[52]  K. Flaherty,et al.  Mechanisms of resistance to immune checkpoint inhibitors , 2018, British Journal of Cancer.

[53]  J. Conejo-Garcia,et al.  PD-1/PD-L1 immune checkpoint inhibitors in advanced cervical cancer. , 2018, Integrative cancer science and therapeutics.

[54]  H. Rugo,et al.  Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  K. Odunsi Immunotherapy in ovarian cancer. , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[56]  A. Gadducci,et al.  Immune Checkpoint Inhibitors in Gynecological Cancers: Update of Literature and Perspectives of Clinical Research. , 2017, Anticancer research.

[57]  Qiaohong Wang,et al.  Prognostic value of tumor PD‐L1 expression combined with CD8+ tumor infiltrating lymphocytes in high grade serous ovarian cancer , 2017, International immunopharmacology.

[58]  Qin Huang,et al.  Membranous and Cytoplasmic Expression of PD-L1 in Ovarian Cancer Cells , 2017, Cellular Physiology and Biochemistry.

[59]  S. Pignata,et al.  Immunotherapy in ovarian, endometrial and cervical cancer: State of the art and future perspectives. , 2017, Cancer treatment reviews.

[60]  A. Jazaeri,et al.  Immunotherapy in Gynecologic Cancers: Are We There Yet? , 2017, Current Treatment Options in Oncology.

[61]  R. Uppaluri,et al.  Checkpoint immunotherapy in head and neck cancers , 2017, Cancer and Metastasis Reviews.

[62]  Giorgio Valabrega,et al.  Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity , 2017, Oncotarget.

[63]  Opal L. Reddy,et al.  Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas , 2017, Diagnostic Pathology.

[64]  R. Ashfaq,et al.  Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. , 2017, The Lancet. Oncology.

[65]  E. Schmidt,et al.  A phase Ib/II trial of lenvatinib (LEN) plus pembrolizumab (Pembro) in patients (Pts) with endometrial carcinoma. , 2017 .

[66]  L. Molinero,et al.  Clinical activity, safety and biomarker results from a phase Ia study of atezolizumab (atezo) in advanced/recurrent endometrial cancer (rEC). , 2017 .

[67]  C. le Tourneau,et al.  Pembrolizumab in cervical cancer: latest evidence and clinical usefulness , 2017, Therapeutic advances in medical oncology.

[68]  S. Jordan,et al.  Epidemiology of epithelial ovarian cancer. , 2017, Best practice & research. Clinical obstetrics & gynaecology.

[69]  T. Kessler,et al.  Cervical Cancer: Prevention and Early Detection. , 2017, Seminars in oncology nursing.

[70]  K. Goldberg,et al.  FDA Approval Summary: Atezolizumab for the Treatment of Patients with Progressive Advanced Urothelial Carcinoma after Platinum‐Containing Chemotherapy , 2017, The oncologist.

[71]  J. Bedke,et al.  [First-line therapy in advanced renal cell carcinoma : A randomized, open-label phase III study evaluating the efficacy and safety of pembrolizumab (MK-3475) in combination with axitinib compared to sunitinib monotherapy as first-line treatment for locally advanced or metastatic renal cell carcinoma , 2017, Der Urologe. Ausg. A.

[72]  H. Rexer,et al.  Erstlinientherapie beim fortgeschrittenen Nierenzellkarzinom , 2017, Der Urologe.

[73]  R. Kiessling,et al.  Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma , 2017, Oncotarget.

[74]  A. Oza,et al.  Treatment strategies for endometrial cancer: current practice and perspective , 2017, Current opinion in obstetrics & gynecology.

[75]  J. Sosman,et al.  Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma , 2017, Cell.

[76]  C. Robert,et al.  Renal effects of immune checkpoint inhibitors , 2016, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[77]  J. Berek,et al.  Immunotherapy in ovarian cancer. , 2017, Current problems in cancer.

[78]  M. Brewer,et al.  Endometrial Cancer: Is This a New Disease? , 2017, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

[79]  J. Cave,et al.  Outcome and Biomarker Analysis from a Multicenter Phase 2 Study of Ipilimumab in Combination with Carboplatin and Etoposide as First-Line Therapy for Extensive-Stage SCLC , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[80]  Gennaro Ciliberto,et al.  Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: New candidates for checkpoint blockade immunotherapy? , 2016, Cancer treatment reviews.

[81]  D. Jäger,et al.  Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. , 2016, The Lancet. Oncology.

[82]  Qiuyang Zhang,et al.  Expression of PD-1, PD-L1 and PD-L2 is associated with differentiation status and histological type of endometrial cancer , 2016, Oncology letters.

[83]  Melissa L. Johnson,et al.  A first-in-human study of REGN2810, a monoclonal, fully human antibody to programmed death-1 (PD-1), in combination with immunomodulators including hypofractionated radiotherapy (hfRT). , 2016 .

[84]  S. Rosenberg,et al.  A High-avidity WT1-reactive T-Cell Receptor Mediates Recognition of Peptide and Processed Antigen but not Naturally Occurring WT1-positive Tumor Cells , 2016, Journal of immunotherapy.

[85]  S. Narod,et al.  Can advanced-stage ovarian cancer be cured? , 2016, Nature Reviews Clinical Oncology.

[86]  Michael M. Braun,et al.  Diagnosis and Management of Endometrial Cancer. , 2016, American family physician.

[87]  P. Tsikouras,et al.  Cervical cancer: screening, diagnosis and staging. , 2016, Journal of B.U.ON. : official journal of the Balkan Union of Oncology.

[88]  Lauren L. Ritterhouse,et al.  Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer , 2016, Oncotarget.

[89]  A. Santin,et al.  Immunotherapy and targeted therapy for cervical cancer: an update , 2016, Expert review of anticancer therapy.

[90]  B. Karlan,et al.  OVARIAN CANCER , 2016, Nature Reviews Disease Primers.

[91]  R. Eskander,et al.  Immunotherapy in endometrial cancer - an evolving therapeutic paradigm , 2015, Gynecologic Oncology Research and Practice.

[92]  K. Okamoto,et al.  Abstract A92: Effects of lenvatinib on tumor-associated macrophages enhance antitumor activity of PD-1 signal inhibitors , 2015 .

[93]  S. Ghaem-Maghami,et al.  Does fertility treatment increase the risk of uterine cancer? A meta-analysis. , 2015, European journal of obstetrics, gynecology, and reproductive biology.

[94]  K. Yamaguchi,et al.  Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[95]  A. Zlotnik,et al.  B cells responses and cytokine production are regulated by their immune microenvironment. , 2015, Cytokine.

[96]  D. Powell,et al.  Tumor infiltrating lymphocytes in ovarian cancer , 2015, Cancer biology & therapy.

[97]  A. Waxman,et al.  Cervical cancer prevention: immunization and screening 2015. , 2015, The Medical clinics of North America.

[98]  M. Alimohammadian,et al.  Comparative Analysis of CD4+ and CD8+ T Cells in Tumor Tissues, Lymph Nodes and the Peripheral Blood from Patients with Breast Cancer , 2015, Iranian biomedical journal.

[99]  R. Emerson,et al.  PD-1 blockade induces responses by inhibiting adaptive immune resistance , 2014, Nature.

[100]  J. Farley,et al.  MEK1/2 inhibitors in the treatment of gynecologic malignancies. , 2014, Gynecologic oncology.

[101]  D. Giugliano,et al.  Metabolic syndrome and endometrial cancer: a meta-analysis , 2014, Endocrine.

[102]  W. Park,et al.  Valproic acid inhibits the growth of HeLa cervical cancer cells via caspase-dependent apoptosis. , 2013, Oncology reports.

[103]  Carolyn Rooth Ovarian cancer: risk factors, treatment and management. , 2013, British journal of nursing.

[104]  Lieping Chen,et al.  Molecular mechanisms of T cell co-stimulation and co-inhibition , 2013, Nature Reviews Immunology.

[105]  R. Barakat,et al.  Contemporary quality of life issues affecting gynecologic cancer survivors. , 2012, Hematology/oncology clinics of North America.

[106]  A. Brandes,et al.  Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[107]  Xin Li,et al.  [Clinical features and prognosis of cervical cancer in young women]. , 2010, Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences.

[108]  A. Mutirangura,et al.  Targeted therapies for rare gynaecological cancers. , 2010, The Lancet. Oncology.

[109]  G. Tortora,et al.  EGFR antagonists in cancer treatment. , 2008, The New England journal of medicine.

[110]  Ekaterina S Jordanova,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. , 2007, Cancer research.

[111]  J. Carter,et al.  An overview of uterine cancer and its management , 2006, Expert review of anticancer therapy.

[112]  George Coukos,et al.  Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. , 2003, The New England journal of medicine.

[113]  Eileen M. Burd,et al.  Human Papillomavirus and Cervical Cancer , 1988, The Lancet.

[114]  B. Modan,et al.  Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[115]  S. Orsulic,et al.  Ovarian Cancer , 1993, British Journal of Cancer.

[116]  F. Denizot,et al.  A new member of the immunoglobulin superfamily—CTLA-4 , 1987, Nature.

[117]  S. Aaronson,et al.  Isolation of a new human oncogene from a diffuse B-cell lymphoma , 1985, Nature.

[118]  L. Brandes,et al.  IMMUNOTHERAPY FOR OVARIAN CANCER , 1976, The Lancet.