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Pembrolizumab for anaplastic thyroid cancer: a case study

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Abstract

Blockade of the PD-1/PD-L1 pathway with targeted monoclonal antibodies has demonstrated encouraging anti-tumour activity in multiple cancer types. We present the case of a patient with BRAF-negative stage IVC anaplastic thyroid cancer (ATC) treated with the anti-PD-1 monoclonal antibody, pembrolizumab, following radiographic progression on chemoradiation. Blood samples were collected prior to and at four time points during treatment with pembrolizumab. Mass cytometry was used to determine expression of relevant biomarkers by peripheral blood mononuclear cells. Faecal samples were collected at baseline and 4 weeks following treatment initiation; taxonomic profiling using 16S ribosomal RNA (rRNA) gene sequencing was performed. Following treatment, a marked expansion in CD20+ B cell, CD16+ CD56lo NK cell and CD45RO+ CCR7+ central memory CD4+ T-cell populations was observed in the peripheral blood. Proportions of cells expressing the co-receptors TIGIT, OX40 and CD86 also increased during treatment. A high abundance of bacteria of the order Bacteroidales, specifically from the Bacteroidaceae and Rikenellaceae families, was identified in the faecal microbiota. Moreover, the patient’s microbiome was enriched in Clostridiales order members Ruminococcaceae, Veillonellaceae and Lachnospiraceae. Alpha diversity of the gut microbiome was significantly higher following initiation of checkpoint therapy as assessed by the Shannon and Simpson index. Our results suggest that treatment with pembrolizumab promotes expansion of T-, B- and NK cell populations in the peripheral blood at the time of tumour regression and have the potential to be implemented as predictive biomarkers in the context of checkpoint blockade therapy. Larger studies to confirm these findings are warranted.

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Abbreviations

AJCC:

American Joint Committee on Cancer

ATC:

Anaplastic thyroid cancer

BBB:

Blood–brain barrier

Bregs:

Regulatory B cells

CNS:

Central nervous system

CONCERT:

Centre for Oncology Education and Research Translation

CT:

Computed tomography

CTC:

Circulating tumour cells

EBRT:

External beam radiation therapy

FDG:

Fluorodeoxyglucose

FNA:

Fine needle aspiration

HL:

Hodgkin’s lymphoma

IMRT:

Intensity-modulated radiation therapy

irAEs:

Immune-related adverse events

MMT:

Multimodal therapy

NLR:

Neutrophil:lymphocyte ratio

pDCs:

Plasmacytoid dendritic cells

PET/CT:

Positron emission tomography/computed tomography

RCC:

Renal cell carcinoma

sOTUs:

Individual sequence variants

Tfh:

Follicular T-helper cells

TPS:

Tumour proportion score

WBRT:

Whole-brain radiation therapy

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Funding

This research was funded by the Ingham Institute for Applied Medical Research Circulating Tumour Cells (CTC) Head and Neck Research Grant, Liverpool Hospital and Cancer Council NSW (APP1147099) HM is the recipient of the Early Career Fellowship (GNT1037298).  TLR is the recipient of a Cancer Institute New South Wales Future Research Leader Fellowship and salary support from Cancer Institute NSW (CINSW) translational cancer research centre CONCERT.

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Authors and Affiliations

  1. Ingham Institute for Applied Medical Research, 1 Campbell St, Liverpool, NSW, 2170, Australia

    Marra Jai Aghajani, Paul de Souza, Navin Niles & Tara Laurine Roberts

  2. School of Medicine, Western Sydney University, Campbelltown, NSW, Australia

    Marra Jai Aghajani, Adam Cooper, Kasim Ismail, Paul de Souza, Navin Niles & Tara Laurine Roberts

  3. Liverpool Cancer Therapy Centre, Corner of Goulburn and Elizabeth Streets, Liverpool, NSW, 2170, Australia

    Adam Cooper & Victoria Bray

  4. Discipline of Pathology, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

    Helen McGuire & Barbara Fazekas de St Groth

  5. Ramaciotti Facility for Human Systems Biology, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia

    Helen McGuire & Barbara Fazekas de St Groth

  6. Hawkesbury Institute for the Environment, Western Sydney University, Penrith, NSW, Australia

    Thomas Jeffries

  7. School of Science and Health, Western Sydney University, Penrith, NSW, Australia

    Thomas Jeffries

  8. Sydney South West Pathology Services, Liverpool Hospital, Liverpool, NSW, Australia

    Jawad Saab & Kasim Ismail

  9. South West Sydney Clinical School, UNSW Sydney, Sydney, NSW, Australia

    Paul de Souza & Tara Laurine Roberts

  10. Department of Head and Neck Surgery, Liverpool Hospital, Liverpool, NSW, Australia

    Navin Niles

  11. Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia

    Navin Niles

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  1. Marra Jai Aghajani
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  2. Adam Cooper
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  11. Tara Laurine Roberts
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Contributions

Study conception and design was done by TLR, PS, VB, MJA, AC, HM, NN, BFSG. Experiments were performed and analysed by TLR, MJA, HM, TJ. Clinical data and samples were prepared and interpreted by TLR, AC, MJA, JS, KI. All authors made substantial contributions to data interpretation, manuscript preparation and review.

Corresponding author

Correspondence to Marra Jai Aghajani.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

All research was performed under Human Research ethics committee (HREC) protocols from Liverpool Hospital (Project number 13/097, HREC/13/LPOOL/158) (South West Sydney Local Health District), facilitated by the Centre for Oncology Education and Research Translation (CONCERT) Biobank, in accordance with relevant legislation [81].

Informed consent

Written informed consent was obtained from the patient who is the subject of the case study on January 10th, 2018. The patient agreed to the publication of this case study and the use of their specimens (provided that the participant could not be identified). Written informed consent was obtained from all controls prior to the study.

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Aghajani, M.J., Cooper, A., McGuire, H. et al. Pembrolizumab for anaplastic thyroid cancer: a case study. Cancer Immunol Immunother 68, 1921–1934 (2019). https://doi.org/10.1007/s00262-019-02416-7

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  • DOI: https://doi.org/10.1007/s00262-019-02416-7

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