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Molecular Oncology & Immunology: Christian Blank

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Christian Blank, dr.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 in which situations 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 decrease 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 that that while combination of BRAF and MEK inhibition improved tumor control, BRAF inhibitors impaired tumor immune infiltration and did not synergize with T cell checkpoint blockade by anti-PD-1, -PD-L1 and -CTLA-4 mAb. Current experiments aim at understanding the mechanism of BRAF inhibitor-mediated decrease of tumor immune infiltration.

Identification of tools for TIL

Aside the blockade of co-inhibitory molecules, adoptive transfer of tumor specific T cells has been a promising therapy approach. However, as with the othert immunotherapies the response percentage of such a therapy is low and promising results have been observed so far only in melanoma patients. Therefore we are currently exploring approaches to improve expansion of tumor infiltrating lymphocytes (TIL) from renal cell carcinoma (RCC).

Co-workers

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Marcel Deken, MSc

Ph.D. Student

Experience

Preclinical investigation of combining immunotherapy with targeted therapy.

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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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Valenti, Mesele

Mesele Valenti

Research Technician

Experience

I studied Biology in the University of Athens, Greece and I completed my MSc in Molecular and Applied Physiology in the Medical School of Athens in 2011. Since then I have been working in cardiovascular research at ELPEN Experimental Center in Athens, Greece and at TEMPLE University in Philadelphia, USA. I recently changed my path in research, switching to Immunology that was always my passion. Following that, I joined Christian Blank's group as Research Technician, on September 2016. Our main aim in the lab is to identify mechanisms of tumor immune escape combining immunotherapy with targeted therapies in human melanoma. 

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Key publications View All Publications

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

    Cancer, 2011 May 15;117

    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

  • Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.

    Science. 2015;350:207-11

    Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Foppen MH, Goldinger SM, Utikal J, Hassel JC, Weide...

    Link to pubmed
  • Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma.

    Cancer Immunol Immunother. 2015;64:1241-50.

    Guislain A, Gadiot J, Kaiser A, Jordanova ES, Broeks A, Sanders J, van Boven H, de Gruijl TD, Haanen JB, Bex A, Blank CU.

    Link to pubmed
 

Contact

  • Office manager

    Renske Muns-de Jong

  • E-mail

    rm.d.jong@nki.nl

  • Telephone Number

    +31 20 512 2055

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