PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives

doi:10.1007/s11684-018-0674-4

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 Li^1,²(

)

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 Author(s): 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.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0674-4
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I4/438

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.

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.

Tab.2 PD-1- and PD-L1-blocking agents in clinical development

Target	Agent	Clinical indication and ongoing evaluation	Stage of development
PD-1	Nivolumab (BMS-9336558, MSX1106, ONO-4538, Opdivo^®)	*NCT02257528: treating persistent, recurrent, and metastatic CC	Phase II
		*NCT02465060: treating patients with mismatch repair deficiency (loss of MLH1 or MSH2 by IHC) in advanced refractory solid tumors	Phase II
		*NCT02379520: HPVST cells alone or in combination with nivolumab in HPV-related carcinoma	Phase I
		*NCT03126110:INCAGN01876+ nivolumab or/and ipilimumab treating advanced or metastatic malignancies	Phase I/II
		*NCT03241173:INCAGN01949+ nivolumab or/and ipilimumab treating advanced or metastatic malignancies	Phase I/II
		*NCT03298893: in combination with radiotherapy and cisplatin in locally advanced CC	Phase I
		*NCT02628064: treating advanced solid tumors including CC	Phase II
			Phase II
	Pembrolizumab (MK3475, Keytruda^®)	*NCT02628067: treating advanced solid tumors including CC	Phase II
		*NCT02635360: in combination with chemoradiation for the treatment of advanced CC	Phase II
		*NCT03144466: in combination with radiotherapy and cisplatin treating advanced CC	Phase I
		*NCT03192059: in combination with radiation and an immune modulatory cocktail treating advanced and/refractory CC endometrial carcinoma or uterine sarcoma	Phase II
		*NCT02858310: TCR gene therapy targeting HPV-16 E7 with or without pembrolizumab for HPV-associated cancers	Phase I
		*NCT03444376: in combination of GX-188E vaccination treating advanced, nonresectable HPV16 and/or 18+ CC	Phase Ib-II
		*NCT03635567: in combination with chemotherapy treating persistent, recurrent, or metastatic CC	Phase III
		*NCT03367871: in combination with chemotherapy and bevacizumab treating CC	Phase II

PD-L1	Atezolizumab (MDPL-3280A, Tecentrip^®)	*NCT02921269: in combination with bevacizumab treating recurrent, persistent, or metastatic CC	Phase II
		*NCT03074513: in combination with bevacizumab treating rare solid tumors including CC	Phase II
		*NCT03073525: in combination with Vigil treating advanced gynecological cancers	Phase II
		*NCT02914470: in combination with carboplatin-cyclophosphamide treating advanced breast cancer and gynecologic cancer	Phase I
		*NCT03614949: in combination with stereotactic body radiation therapy treating recurrent, persistent, or metastatic CC	Phase II
		*NCT03340376: in combination with doxorubicin treating recurrent CC	Phase II
			Phase II
	Avelumab (MSB0010718C, BAVENCIO®)	*NCT03260023: in combination with TG4001 treating HPV-16+ recurrent or metastatic malignancies	Phase I/II
	Avelumab (MSB0010718C, BAVENCIO®)	*NCT03217747: in combination with or without radiation, or radiation and cisplatin treating limited, locally advanced or metastatic solid tumors including CC	Phase I/II
	Durvalumab (MEDI4736)	*NCT01975831: in combination with tremelimumab treating advanced solid tumors	Phase I
		*NCT02725489:in combination with Vigil and durvalumab treating advanced women's cancers	Phase II
		*NCT02291055: in combination with ADXS11-001 in previously treated locally advanced or metastatic cervical or HPV+ head and neck cancer	Phase I/II
		*NCT03452332: in combination with stereotactic ablative radiotherapy and tremelimumab treating cervical, vaginal, or vulvar cancer	Phase I

Tab.3 Ongoing PD pathway-targeted clinical trials of subjects with CC

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