1. Vacatures
  2. Radboud University Medical Center (Radboudumc)
  3. PhD candidate ‘Harnessing the immune system in myelodysplastic syndromes: combining hypomethylating agents with dendritic cell vaccination’

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PhD candidate ‘Harnessing the immune system in myelodysplastic syndromes: combining hypomethylating agents with dendritic cell vaccination’

This project focuses on the preclinical exploration of novel immunotherapies against Myelodysplastic syndromes (MDS).

10 maanden geleden

Arbeidsvoorwaarden

Standplaats:
Landelijk / geen vaste standplaats
Dienstverband:
Tijdelijk contract / Tijdelijke opdracht
Uren per week:
36 uur
Opleidingsniveau:
WO

Functieomschrijving

This project focuses on the preclinical exploration of novel immunotherapies against Myelodysplastic syndromes (MDS). Long-term outcome is poor for patients with MDS due to progressive bone marrow failure and leukemia development. Importantly, immunotherapeutic approaches, including allogeneic stem cell transplantation, have demonstrated curative potential. However, most MDS patients are unfit to receive stem cell transplantation due to their high age and/or frailty. This emphasizes the need for more specific and tolerable immunotherapies to prevent disease progression and improve overall survival.

In order to develop clinical effective immunotherapeutic strategies, key players within the suppressive MDS bone marrow environment underlying defective anti-tumor immunity should be deciphered. We and others have observed increased frequencies of suppressive immune cells, including myeloid-derived suppressor cells and regulatory T cells, which are involved in the immune escape of the (pre-)leukemic cells via secretion of immunosuppressive factors and inhibition of T and Natural Killer (NK) cell responses. In addition to this immune misbalance, DNA hypermethylation, leading to epigenetic silencing of tumor suppressor genes, plays an important role in MDS and leukemia oncogenesis.

Currently, higher-risk MDS patients receive hypomethylating agents (HMA) as standard of care. Interestingly, HMA not only exert strong anti-leukemic effects, but also possess immune promoting properties. It has been shown that HMA enhance expression of tumor antigens, modulate expression levels of immune stimulatory and inhibitory molecules, and can prime and potentiate tumor-reactive T and NK cell responses.

To further boost and support these tumor-reactive immune responses dendritic cell (DC) vaccination therapy is highly attractive. Natural occurring myeloid and plasmacytoid DC (mDC and pDC) subsets have been postulated to possess superior therapeutic efficacy due to their distinct functional properties and cross-talk capacity. However, in MDS patients the numbers and functionality of DC is severely impaired, limiting the possibilities for DC isolation from apheresis material. Nonetheless, we recently developed an innovative ex vivo culture protocol to generate high numbers of mDC and pDC from CD34+ hematopoietic progenitor cells with superior capacity to boost tumor-reactive T and NK cell responses.

Functie-eisen

  • Masters degree in (Medical) Biology, Biomedical sciences or Molecular life sciences;
  • Ample experience in cell culture, flow cytometry and cellular immunology techniques;
  • Art. 9 degree in animal studies is a prerequisite;
  • Enthusiasm and ambition to succeed in academic and translational research;
  • Highly motivated to work in an interdisciplinary environment at the cutting edge of science;
  • Well-developed social skills directed to work in a team, excellent interpersonal and communicative skills;
  • You recognise yourself in the Radboud way of working.

Tasks and responsibilities

  • The PhD candidate contributes to the development of new knowledge within the context of the department’s research program;
  • Designs and performs scientific research;
  • Writes scientific publications and presents findings at scientific meetings;
  • Works in a team with clinical and non-clinical PhD candidates and scientists;
  • Discusses, plans and performs research in a stimulating environment;
  • Works in a highly international research group.
  • Masters degree in (Medical) Biology, Biomedical sciences or Molecular life sciences;
  • Ample experience in cell culture, flow cytometry and cellular immunology techniques;
  • Art. 9 degree in animal studies is a prerequisite;
  • Enthusiasm and ambition to succeed in academic and translational research;
  • Highly motivated to work in an interdisciplinary environment at the cutting edge of science;
  • Well-developed social skills directed to work in a team, excellent interpersonal and communicative skills;
  • You recognise yourself in the Radboud way of working.

Aim of the research project

The aim of this pre-clinical research project is to further unravel immunosuppressive mechanisms involved in defective anti-tumor immunity in the MDS bone marrow environment. Furthermore, we will extensively examine immunomodulatory effects of HMA treatment on T and NK cell function in MDS patients. Finally, we will explore the potency of HMA and DC treatment to prime and boost tumor-reactive T and NK cell responses. We anticipate that this novel combination therapy could lead to the establishment of long-lasting disease control and potentially cure of patients without causing severe toxicity. With these pre-clinical studies we aim to generate rationale for further clinical investigation in MDS patients. You will participate in the RIMLS.

Conditions

Salary is € 2279 gross per month in the first year up to a maximum of € 2919 gross per month in the last fourth year, plus additional vacation bonus (8% per year) and end of year payments (8.3% per year).

Additional information

Terms of employment

  • This four-year project should culminate in a PhD thesis;
  • Salary is € 2279 gross per month in the first year up to a maximum of € 2919 gross per month in the last fourth year, plus additional vacation bonus (8% per year) and end of year payments (8.3% per year);
  • Upon commencement of employment we require a certificate of conduct (Verklaring Omtrent het Gedrag, VOG). Radboud university medical center’s HR Department will apply for this certificate on your behalf;
  • Read more about the Radboudumc employment conditions.


Application
We request applicants to send a letter of intent outlining special interest in the position, overall related qualifications, experience and career goals, a curriculum vitae and names and addresses of professional references.

Information
Additional information about the vacancy can be obtained from Dr. Willemijn Hobo, assistant professor at the Department of Laboratory Medicine and Dr. Harry Dolstra, associate professor. Use the Apply button to submit your application.

Bedrijfsomschrijving

Radboudumc strives to be a leading developer of sustainable, innovative and affordable healthcare to improve the health and wellbeing of people and society in the Netherlands and beyond. This is the core of our mission: To have a significant impact on healthcare. To get a better picture of what this entails, check out our strategy film.

Our key strength is medical life-sciences and clinical practice, with an impressive infrastructure comprising state-of-the-art technology platforms and (translational) research facilities. The Radboudumc is therefore uniquely positioned in the emerging Euregio and Dutch healthcare infrastructure to play a leading role in the new healthcare paradigm of prediction, prevention and personalised medicine.

The Radboudumc focuses on scientific health challenges of today, with an eye on emerging diseases of the future.

Read more about what it means to work at Radboudumc and how you can do your part.

The research project will be conducted in the Immunotherapy research group of the Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. We focus on the characterization and modulation of immune reactions involved in the antitumor response against cancer.

Our translational research program encompasses four intermingled themes:
1) development of novel strategies to boost antitumor immunity after allogeneic stem cell transplantation;
2) co-signaling pathways involved in tumor immune escape;
3) DC-based vaccination strategies against hematological cancers;
4) NK cell-based immunotherapy against leukemia, multiple myeloma and ovarian cancer.

Our research is embedded in the Radboud Institute for Molecular Life Sciences (RIMLS). The studies indicated in this vacancy will be performed in close collaboration with clinicians of the Department of Hematology at the Radboudumc. We provide a stimulating work environment within a group of enthusiastic non-clinical and clinical researchers with a strong national and international research network and track record.