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Molecular Oncology & Immunology: Christian Blank

Blank, Christiaan

Christian Blank, Prof.Group Leader

About Christian Blank

Research interest: Combination of targeted and immunotherapy

Development of inducible murine melanoma models

It is crucial to test new therapeutic approaches in appropriate in vivo models that simulate the human cancer reality. Transplantable tumor models often do not mimic the complex interaction between the tumor cell and the tumor microenvironment and therefore may have little predictive value for the treatment of cancer patients. Inducible or spontaneous murine melanoma models are more physiological, but due to the late onset of tumor formation less practical for long-term immunotherapeutic experiments. We have crossed several strains inheriting typical mutations found in human melanoma to simulate early and late stage disease.We aim to identify mechanisms of tumor immune escape and to develop therapeutic protocols to overcome these. Aside other mechanisms play co-inhibitory molecules a major role in immune escape.

Role of co-inhibitory molecules during tumor immune escape

Appropriate T cell activation depends on TCR ligation and a positive secondary signal. Recent work revealed that this secondary signal is not an on-off phenomenon but a signal of modulated intensity, which is orchestrated by several co-stimulatory and co-inhibitory molecules. We and others have shown that one of the ligands (PD-L1) of one such a co-inhibitory molecule (PD-1) is highly expressed on tumor cells and leads to impaired immune responses. We found an increased PD-L1 expression on metastases compared to primary melanoma in human, but no influence on overall survival, raising the question under which circumstances PD-L1 inhibits tumor specific T cells, which is a current project.

Combination of targeted and immunotherapy

While targeted therapies are thought be not toxic for immune cells, they alter the tumor microenvironment so that increased or decreased tumor immune infiltration can occur. Understanding mechanisms of this indirect immune modulation via targeted agents will provide insights for optimal combinations of these compounds. In a late stage melanoma mouse model we have found that intermittent BRAF and MEK inhibition in combination with PD-1 blockade induced superior response rates, and is currently tested in an early phase trials at the NKI. We found that targeting "other" tumor immune-infiltrating cell subsets can improve tumor control further. Currently we are dissecting these mechanisms of action.

Modulating tumor associated metabolism

Cancers use anaerobic glycolysis despite presence of sufficient oxygen ('Warburg effect'). This effect leads to an acidification of the tumor environment, subsequently inhibiting T cell effector functions. Interfering in the cancer cell metabolism might thus improve anti-tumor immune functions.

 

Co-workers

Dimitriadis, Petros

Petros Dimitriadis

Bioinformatician

Experience

I obtained my Master's degree in Bioinformatics from the joined program between Leiden University and Delft University of technology in 2018. During my master thesis project, I employed deep learning methods to predict early graft loss in renal transplantations.

In July 2019 I joined the Blank group as a Bioinformatician. The main responsibility in my current position is to analyze the data in several different projects of the group.

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Gomes, Tania

Dr. Taina Gomes

Technician

Experience

I studied Physical Therapy in the Federal University of Rio de Janeiro, Brazil and completed my PhD in Biological Chemistry in Federal University of Rio de Janeiro in 2018. During my PhD I studied the role of neutrophils in cancer-associated thrombosis. On June 2019 I joined Christian Blank's group as Research Technician.

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Hoefsmit, Esmee

Esmée Hoefsmit

Ph.D. student

Experience

I studied Biomedical Sciences at the University of Amsterdam. During my Master's I performed internships at the department of experimental immunology, AMC (group of Dr. R. Lutter) and at the lab of Prof. R. A. Weinberg, Whitehead Institute, Boston. After graduated cum laude, I started my PhD in Christian Blank's group in March 2018. My project is focused on tumor infiltration of dendritic cells and natural killer cells in melanoma and checkpoint-inhibitor induced immune-related adverse events.  

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Lacroix, Ruben

Ruben Lacroix MSc

Ph.D. student

Experience

Every age offers opportunities to reach unbelievable goals. We can't be the first to land on the moon anymore, but we can be the generation that develops therapies allowing cancer patients to life for years. Being in the tumor immunology field now, excites me, I can imagine, as much as knowing that we will for the first time put a man on the moon. Currently, I research immune checkpoint modulation in combination with targeted therapies in melanoma, a mix shown to  produce lasting responses. It helps me that the NKI/AVL is filled with the same passion that I have!

Bsc: Life Science & Technology, Msc: biomedical sciences masters (immunology, infectious diseases)

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Rao, Disha

Disha Rao

Ph.D. student

Experience

The success of check-point blockade therapies increased my faith in the concept of utilizing immune modulation to prevent tumor growth. This prompted me to pursue research involving tumor immunology. We are yet to fully understand the effect of certain immune cells on tumor progression. During my PhD, I intend to elucidate the role of B cells in cancer. Previously, I completed Master's in
Biomedicine at Karolinska Institutet, Sweden and Bachelor of Engineering (Biotechnology) at R V College of Engineering, India. I aspire to contribute to the growing field of cancer immunology hoping it will help in finding relevant therapeutic targets.  

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Reijers,Irene 2

Irene Reijers MD

Ph.D. student

Experience

I became acquainted with this institute during my master of medicine, when I investigated the effect of immunotherapy after pretreatment with targeted therapy in patients with metastatic melanoma as part of my research internship.

After graduating medical school at the University of Utrecht, I started my PhD in Christian Blank's group in December 2018. My main project focusses on personalized adjuvant therapy in patients with stage III melanoma, based on pathological responses in a marked lymphnode to neo-adjuvant ipilimumab plus nivolumab.

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Rozeman, Lisette

Lisette Rozeman MD

Ph.D. student

Experience

After finishing medical school at the University of Groningen I worked for one year as a resident at the department of medical oncology in this institute. In 2016 I started my PhD in the Blank group.

My project is focused on improving outcome of melanoma patients upon immunotherapy. During my PhD I am coordinating two clinical trials with the aim to: 1) evaluate whether adding short-term targeted therapy improves outcome of melanoma patients treated with anti-PD-1 2) identify the optimal neo-adjuvant combination scheme of nivolumab and ipilimumab in patients with stage 3 melanoma. Furthermore I will try to identify biomarkers for response upon treatment with anti-PD-1+/-antiCTLA-4.

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Versluis, Judith

Judith Versluis MD

Ph.D. student

Experience

After graduating medical school at the University of Amsterdam, I worked for almost a year as a resident at the department of medical oncology in this institute. I started my PhD in March 2019 in the Blank group. 

During my PhD I will focus on new immunotherapy combinations and identify alternative neoadjuvant combination schemes for biomarker-unfavorable patients.

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Zhou, Juan

Juan Zhou MSc

Technician

Experience

I started my research about neurogenesis and inflammation in Leiden University Medical Centre in 2012. Then I did a PhD project about discovery and identification of novel inhibitors for a N-acyltransferase enzyme in the endocannabinoid system in Leiden University. After that I started working as a research technician in Blank group from May 2019. My main project is finding relative biomarkers to personalize immunotherapies.

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Key publications View All Publications

  • Overall survival and PD-L1 expression in metastasized malignant melanoma.

    Cancer. 2011 May 15;117(10):2192-201.

    Gadiot J, Hooijkaas AI, Kaiser ADM, van Tinteren H,  van Boven H, and Blank C.

    Link to Pubmed
  • PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells.

    Cancer Res. (2004), 1;64(3):1140-5.

    Blank C, Brown I, Peterson AC, Spiotto M, Honjo T, and Gajewski TF.

    Link to Pubmed
 
 

Recent publications View All Publications

  • Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold.

    Cell. 2019 Jul 25;178(3):585-599.e15.

    Vredevoogd DW, Kuilman T, Ligtenberg MA, Boshuizen J, Stecker KE, de Bruijn B, Krijgsman O, Huang X, Kenski JCN, Lacroix R, Mezzadra R, Gomez-Eerland R, Yildiz M, Dagidir I, Apriamashvili G, Zandhuis N, van der Noort V, Visser NL, Blank CU, Altelaar M, Schumacher TN, Peeper DS.

    Link to Pubmed
  • Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.

    Lancet Oncol. 2019 Jul 22. pii: S1470-2045(19)30388-2.

    Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV.

    Link to Pubmed
 

Contact

  • Office manager

    Stephanie Timmer

  • E-mail

    s.timmer@nki.nl

  • Telephone Number

    +31 20 512 2099

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