Checkpoint inhibitors in endometrial cancer: Preclinical rationale and clinical activity

Gloria Mittica, Eleonora Ghisoni, Gaia Giannone, Massimo Aglietta, Sofia Genta, Giorgio Valabrega

Research output: Contribution to journalReview article

24 Citations (Scopus)

Abstract

Context: Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors. Materials and Methods: We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords 'endometrial cancer' and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial. gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types. Results: POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase-1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients. Conclusions: Immune checkpoint inhibitors are an attractive option in POLEultra- mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response.

Original languageEnglish
Pages (from-to)90532-90544
Number of pages13
JournalOncotarget
Volume8
Issue number52
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Endometrial Neoplasms
Microsatellite Instability
Tumor Microenvironment
Tumor-Infiltrating Lymphocytes
Clinical Trials, Phase I
Atlases
Mutation Rate
PubMed
Protein-Tyrosine Kinases
Names
Neoplasms
Clinical Trials
Genome
Antigens
Drug Therapy
Therapeutics
Research

Keywords

  • Endometrial cancer
  • Immunotherapy
  • Microsatellite instability (MSI)
  • Polymerase epsilon (POLE)-ultra-mutated
  • Tumor infiltrating lymphocytes (TILs)

ASJC Scopus subject areas

  • Oncology

Cite this

Checkpoint inhibitors in endometrial cancer : Preclinical rationale and clinical activity. / Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Aglietta, Massimo; Genta, Sofia; Valabrega, Giorgio.

In: Oncotarget, Vol. 8, No. 52, 01.01.2017, p. 90532-90544.

Research output: Contribution to journalReview article

Mittica, Gloria ; Ghisoni, Eleonora ; Giannone, Gaia ; Aglietta, Massimo ; Genta, Sofia ; Valabrega, Giorgio. / Checkpoint inhibitors in endometrial cancer : Preclinical rationale and clinical activity. In: Oncotarget. 2017 ; Vol. 8, No. 52. pp. 90532-90544.
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