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Frontiers of Medicine

Front. Med.    2019, Vol. 13 Issue (4) : 438-450     https://doi.org/10.1007/s11684-018-0674-4
REVIEW
PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives
Yumeng Wang1, Guiling Li1,2()
1. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011,China
2. Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
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Abstract

Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-1/PD-L1-related therapeutic strategies for CC.

Keywords PD-1      PD-L1      immune checkpoint blockade antibody      immunotherapy      cervical cancer     
Corresponding Authors: Guiling Li   
Just Accepted Date: 28 January 2019   Online First Date: 04 March 2019    Issue Date: 02 August 2019
 Cite this article:   
Yumeng Wang,Guiling Li. PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives[J]. Front. Med., 2019, 13(4): 438-450.
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http://journal.hep.com.cn/fmd/EN/10.1007/s11684-018-0674-4
http://journal.hep.com.cn/fmd/EN/Y2019/V13/I4/438
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Guiling Li
Fig.1  In cervical tumor microenvironment, elevated PD-L1 is expressed by tumor cells, tumor-infiltrated immune cells, and stromal cells. The upregulation of the PD-L1 and PD-1 interaction induces T cell anergy, functional exhaustion, and apoptosis. The interaction also increases inhibitory cytokine secretion (such as IL-10 and TGF-b) and favors the conversion of T cells into Tregs. In system immune status, overexpression and activation of the PD1/PD-L1 pathway also exist. Tumors exploit these mechanisms to suppress anti-tumor T cell activity and evade host immunity, facilitating immune evasion and tumor progression. Antibodies targeting the PD-1 pathway, including PD-1 antibodies and PD-L1 antibodies that inhibit the PD-1/PD-L1 or PD-1/PD-L2 interaction, provide antitumor therapy by restoring T cell-mediated immunity.
ConditionsSubtypesPD1/PD-L1 expressionReference
HPV infectionNegative
Positive
-
+/-
[3248]
Histological abnormalityNegative
Positive
-
+/-
CIN gradeI -/+
II+ /++
III++/+++
Pathological typeSCC
++/+++
AC
-/+
MetastasisNegative
++
Positive
+++
Tab.1  Expression of PD-1/PD-L1 in different cervical neoplastic subtypes
Fig.2  Schematic outline showing the interplay of HPV and PD pathway. Persistent HPV infections upregulate PD-1 and PD-L1 expression levels on cervical cells and infiltrated immune cells. Activation and interaction of the PD pathway facilitate CTL dysfunction and exhaustion, negatively influencing HPV clearance. Malignant cervical lesions are formed, and progress with PD-1/PD-L1 expression is further elevated.
TargetAgentAntibody classCompanyApproval
PD-1Nivolumab (BMS-9336558, MSX1106, ONO-4538, Opdivo®)Human IgG4Bristol–Meyers SquibbFDA approved for melanoma, NSCLCa, RCCb, HNSCCc, cHLd, colorectal cancer, urothelial carcinoma
Pembrolizumab (MK3475, Keytruda®)Humanized IgG4MerckFDA approved for melanoma, NSCLC, RCC, cHL, HNSCC, colorectal carcinoma, urothelial carcinoma
AMP-514(MEDI0680)Humanized IgG4MedImmune
AMP-224PD-L2-IgG2a fusion proteinAmplimmune
PD-L1Atezolizumab (MDPL-3280A,Tecentrip®)Human IgG1GenentechFDA approved for urothelial carcinoma, NSCLC
Avelumab (MSB0010718C, BAVENCIO®)Fully Human IgG1Merck SeronoUrothelial carcinoma,MCCe
Durvalumab (MEDI4736, IMFINZI®)Human IgG1AstraZenecaUrothelial carcinoma
MDX1105(BMS-936559)Human IgG4Bristol–Myers Squibb
Tab.2  PD-1- and PD-L1-blocking agents in clinical development
TargetAgentClinical indication and ongoing evaluationStage of development
PD-1Nivolumab (BMS-9336558, MSX1106, ONO-4538, Opdivo®)*NCT02257528: treating persistent, recurrent, and metastatic CCPhase II
*NCT02465060: treating patients with mismatch repair deficiency (loss of MLH1 or MSH2 by IHC) in advanced refractory solid tumorsPhase II
*NCT02379520: HPVST cells alone or in combination with nivolumab in HPV-related carcinomaPhase I
*NCT03126110:INCAGN01876+ nivolumab or/and ipilimumab treating advanced or metastatic malignanciesPhase I/II
*NCT03241173:INCAGN01949+ nivolumab or/and ipilimumab treating advanced or metastatic malignanciesPhase I/II
*NCT03298893: in combination with radiotherapy and cisplatin in locally advanced CCPhase I
*NCT02628064: treating advanced solid tumors including CCPhase II
Pembrolizumab (MK3475, Keytruda®)*NCT02628067: treating advanced solid tumors including CCPhase II
*NCT02635360: in combination with chemoradiation for the treatment of advanced CCPhase II
*NCT03144466: in combination with radiotherapy and cisplatin treating advanced CCPhase I
*NCT03192059: in combination with radiation and an immune modulatory cocktail treating advanced and/refractory CC endometrial carcinoma or uterine sarcomaPhase II
*NCT02858310: TCR gene therapy targeting HPV-16 E7 with or without pembrolizumab for HPV-associated cancersPhase I
*NCT03444376: in combination of GX-188E vaccination treating advanced, nonresectable HPV16 and/or 18+ CCPhase Ib-II
*NCT03635567: in combination with chemotherapy treating persistent, recurrent, or metastatic CCPhase III
*NCT03367871: in combination with chemotherapy and bevacizumab treating CCPhase II
PD-L1Atezolizumab (MDPL-3280A, Tecentrip®)*NCT02921269: in combination with bevacizumab treating recurrent, persistent, or metastatic CCPhase II
*NCT03074513: in combination with bevacizumab treating rare solid tumors including CCPhase II
*NCT03073525: in combination with Vigil treating advanced gynecological cancersPhase II
*NCT02914470: in combination with carboplatin-cyclophosphamide treating advanced breast cancer and gynecologic cancerPhase I
*NCT03614949: in combination with stereotactic body radiation therapy treating recurrent, persistent, or metastatic CCPhase II
*NCT03340376: in combination with doxorubicin treating recurrent CCPhase II
Avelumab (MSB0010718C, BAVENCIO®)*NCT03260023: in combination with TG4001 treating HPV-16+ recurrent or metastatic malignanciesPhase I/II
*NCT03217747: in combination with or without radiation, or radiation and cisplatin treating limited, locally advanced or metastatic solid tumors including CCPhase I/II
Durvalumab (MEDI4736)*NCT01975831: in combination with tremelimumab treating advanced solid tumorsPhase I
*NCT02725489:in combination with Vigil and durvalumab treating advanced women's cancersPhase II
*NCT02291055: in combination with ADXS11-001 in previously treated locally advanced or metastatic cervical or HPV+ head and neck cancerPhase I/II
*NCT03452332: in combination with stereotactic ablative radiotherapy and tremelimumab treating cervical, vaginal, or vulvar cancerPhase I
Tab.3  Ongoing PD pathway-targeted clinical trials of subjects with CC
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