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Tumor Biology & Immunology: Kok, Marleen

Marleen Kok

Marleen Kok, Dr.Junior Group Leader

About Marleen Kok

There is now abundant clinical evidence that the T cells can control the growth of human cancers, however so far only a small subgroup of breast cancer patients seems to have benefit from immunotherapeutic agents such as anti-PD1. Our ambition is two-fold: 1). To develop predictive tests that can be utilized to select breast cancer patients who will benefit from immunotherapy. We strongly belief that both learning lesions from research in more immunogenic tumors such as melanoma as well as unraveling the breast tumor microenvironment and the systemic immune components (in close collaboration with de Visser lab) will be crucial to accomplish this; 2). To explore how we should combine immunotherapy with conventional treatments that can be immunostimulatory such as certain chemotherapies, targeted therapies or irradiation. Via team-science these ambitions will hopefully lead to future personalized breast cancer immunotherapy.

Modulation of the tumor microenvironment to improve response to PD-1 blockade

The response rate of triple negative breast cancer (TNBC) patients to PD-1 blockade is low, highlighting an urgent clinical need for strategies that render the TNBC tumor microenvironment (TME) more sensitive to PD-1 blockade. Immunomodulatory mechanisms have been proposed for both chemotherapy and irradiation, but it has not been established whether these therapies may improve efficacy of PD-1 blockade by favorably changing the TME. Patients with metastatic TNBC were randomized to anti-PD1 without induction or to one of four induction treatments, consisting of irradiation or a two- week low-dose regimen of cyclophosphamide, cisplatin or doxorubicin, all followed by anti-PD-1. The majority of clinical responses were observed on anti-PD1 in the cisplatin and doxorubicin induction cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes, involved in PD-1/PD-L1, and T-cell cytotoxicity pathways. This was supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNFα-signaling after doxorubicin. In addition, we observed a trend towards increased T-cell infiltration, measured using T-cell receptor (TCR) sequencing, after doxorubicin. Together, the  data suggest that short-term doxorubicin and cisplatin may induce a more favorable TME and increase the likelihood of response to PD-1 blockade in TNBC. Results have been presented at ESMO 2017, ASCO 2018 and recently published in Nature Medicine (Voorwerk et al.)

Immune-related invasive lobular breast cancer

Recently, genomic profiling showed that within invasive lobular breast cancer (ILC) an 'immune-related' subtype exists of tumors with higher expression of immune-related genes. Besides, in a previously established mouse model for mILC, a synergistic effect of platinum and checkpoint inhibitors was observed (dr Karin de Visser group, NKI). Currently we are investigating the efficacy and immunomodulatory capacity of PD-1 blockade in combination with platinum agents in patients with metastatic ILC.

Systemic immune characteristics in breast cancer patients (in collaboration with de Visser lab)

There is now substantial evidence from preclinical studies that suppressive immune cells and soluble immune mediators can blunt the anti-cancer T cells response. Right now the key question is whether this immunosuppressive phenomenon is present in breast cancer patients and whether it is important for response to immunotherapy. In collaboration with the group of dr Karin de Visser we have set-up a pipeline for comprehensive analyses of these systemic immunosuppressive components using high-dimensional flow cytometry combined with functional assays on fresh material from breast cancer patients.

Co-workers

Bakker, Noor.jpg

Noor Bakker

Ph.D. student

Experience

I studied Biomolecular Sciences at the VU Amsterdam. After obtaining my master's degree, I worked for 5 years as a technician in the GMP therapeutic production facility of the NKI were we produced e.g. TILs. In addition, I was involved in several translational research projects in collaboration with the groups of Ton Schumacher and John Haanen, and responsible for the immunomonitoring of a phase I/II clinical vaccination trial.

I am currently a PhD student in the lab of Karin de Visser, in close collaboration with Marleen Kok. My research project is focused on assessing the influence of tumor subtype, tumor stage and (immuno)therapy response on the intratumoral and systemic immune landscape of breast cancer patients.

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Duijst, Maxime

Maxime Duijst

Technician

Experience

I obtained my General Biology bachelor's degree at the University of the District Columbia, Washington DC, followed by completing the master 'Infection & Immunity" at Utrecht University, Utrecht in 2018.

Throughout 2018, I worked at the National Institute of Health (RIVM) working on several projects concerning lung diseases by developing B cell and T cell assays, mainly using flow cytometry.

As my research interest is very broad, I joined the project of Karin de Visser and Marleen Kok in February 2019 to study the relationship between, and the effect of the combination of chemotherapy with checkpoint inhibition, on suppressive immune cells and cancer cells isolated from metastatic breast cancer patients.

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Isaeva, Olga

Olga Isaeva

Ph.D. student

Experience

I am a motivated cancer immunologist, looking to apply computational methods to tumor microenvironment data.

I obtained my BSc in Cell Biology from Moscow State University and my MSc in Bioinformatics from Skolkovo Institute of Science and Technology. During my MSc studies I did an internship at Memorial Sloan Kettering Cancer Center. Also, for three years I worked as a research analyst for a cancer immunology start-up, BostonGene.

At the NKI I work in the groups of Dr. Pia Kvistborg, Dr. Marleen Kok and Dr. Lodewyk Wessels, exploring functional changes in tumor microenvironment and transformed cells during tumor progression and in response to therapy.

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Klaver, Chris

Chris Klaver

Technician

Experience

In November 2018 I joined a project of Karin de Visser and Marleen Kok to analyze immune suppressive cascades in metastatic breast cancer patients and see how these cascades affects the effector immune cells and the success of immune checkpoint blockade.

During my bachelor I developed a strong interest in oncology so I started the master Oncology at the VU Amsterdam. I was trained at the NKI in the lab of prof. Gerrit Meijer, exploring utility of liquid biopsies for colorectal cancer. Afterwards, I did my internship at prof. Maria Rescigno's lab in Milan, where we analyzed the role of bacteria in the metastatic process of colorectal and breast cancer.

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Maaken, Michiel de.jpg

Michiel de Maaker, Ing.

Technician

Experience

In august 2012, I started as technician on the Young Boost trial.
The main objective of the trial is to compare the effect of a high boost dose (26 Gy) with a low boost dose (16 Gy) in breast conserving therapy, on the local recurrence rate.
 Additional objectives are:
To test the genotypic and phenotypic profiles of breast tumors in young patients with invasive breast cancer, and its relation to:
a. Local recurrence after breast conserving treatment
b. Lymph node metastases
c. Distant metastases and survival
d. Radio sensitivity
e. Age

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Nederlof, Iris

Iris Nederlof

Ph.D. Student

Experience

In October 2017 I graduated from medical school and
biomedical sciences at the Leiden University. Currently, I am a PhD student at
the division of molecular pathology. My research focuses on genetic properties
of breast carcinomas and the associations with cancer-immune interactions. I
will work on the 'TONIC trial', 'BASIS cohort' and the 'Young boost trial'
among other projects.

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Voorwerk, Leonie

Leonie Voorwerk MD

Ph.D. student

Experience

I finished my bachelor Biomedical Sciences at the VU Amsterdam in 2012 and I graduated from medical school at the University of Amsterdam in 2016. Before I started my PhD in July 2017 in the group of Marleen Kok, I worked for 6 months as a junior resident at the Antoni van Leeuwenhoek hospital.

My research focuses on exploring strategies to improve immunotherapy for patients with metastatic breast cancer. We examine this by combining immunotherapy with conventional treatments, such as in the TONIC-trial and the GELATO-trial. By comprehensive assessment of the tumor microenvironment and immune cells in peripheral blood, we aim to gain more insight in the immune landscape of breast cancer patients and how this is affected by treatment.

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Key publications View All Publications

  • Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes.

    Breast Cancer Res. 2019 Aug 7;21(1):90.

    Sobral-Leite M, Salomon I, Opdam M, Kruger DT, Beelen KJ, van der Noort V, van Vlierberghe RLP, Blok EJ, Giardiello D, Sanders J, Van de Vijver K, Horlings HM, Kuppen PJK, Linn SC, Schmidt MK, Kok M.

    Link to Pubmed
  • Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

    Nat Med. 2019 Jun;25(6):920-928.

    Voorwerk L, Slagter M, Horlings HM, Sikorska K, van de Vijver KK, de Maaker M, Nederlof I, Kluin RJC, Warren S, Ong S, Wiersma TG, Russell NS, Lalezari F, Schouten PC, Bakker NAM, Ketelaars SLC, Peters D, Lange CAH, van Werkhoven E, van Tinteren H, Mandjes IAM, Kemper I, Onderwater S, Chalabi M, Wilgenhof S, Haanen JBAG, Salgado R, de Visser KE, Sonke GS, Wessels LFA, Linn SC, Schumacher TN, Blank CU, Kok M.

    Link to Pubmed
 
 

Recent publications View All Publications

  • How I treat MSI cancers with advanced disease.

    ESMO Open. 2019 May 21;4(Suppl 2):e000511.

    Kok M, Chalabi M, Haanen J.

    Link to Pubmed
  • Cryoablation and immunotherapy: an overview of evidence on its synergy.

    Insights Imaging. 2019 May 20;10(1):53.

    Aarts BM, Klompenhouwer EG, Rice SL, Imani F, Baetens T, Bex A, Horenblas S, Kok M, Haanen JBAG, Beets-Tan RGH, Gómez FM.

    Link to Pubmed
 

Contact

  • Office manager

    Karin van der Heijden

  • E-mail

    k.vd.heijden@nki.nl

  • Telephone Number

    +31 20 512 2055

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