Postdoc ‘Off-the-shelf stem cell-derived NK cells with chimeric antigen receptors and transpresented interleukin 15 to improve immunotherapy in ovarian cancer patients’

This project focuses on the development of a Good Manufacturing Practice (GMP) compliant platform to generate genetically engineered off-the-shelf allogeneic Natural killer (NK) cell therapy against Ovarian carcinoma (OC). OC is the most lethal gynecological malignancy and accounts for around 1,000 deaths in The Netherlands annually. Due to late diagnosis, most woman relapse after treatment, resulting in a 5-year survival of only 28-46%. As most woman with relapsed or metastatic cancer will die of progressive disease, there is a need for new therapeutic strategies. Adoptive allogeneic NK cell transfer can be an attractive treatment option for adjuvant immunotherapy.

Previously, we have developed a unique GMP-compliant culture system for the manufacturing of allogenic NK cell products from umbilical cord blood derived CD34+ progenitor cells. These products display high purity and a potent anti-OC reactivity in vitro and in vivo and are currently being investigated in a first in human trial. To improve scalability, accessibility and cost-effectiveness, this project focuses on greatly upscaling the NK culture process and cryopreserving them for on-demand application. To further improve the clinical efficacy in OC patient, we will engineer these cells with chimeric antigen receptors (CARs) and transpresented IL15/IL15Rα to improve tumor targeting and NK cell persistence.

You will work on optimizing the culture process for the generation of large numbers of NK cells in a new bioreactor system and translate this to a GMP compliant protocol. Furthermore, you will optimize the cryopreservation and work on the genetic engineering of these cells using lentiviral transduction. The effectiveness of the NK cells will be evaluated in vitro using our established methods, including flowcytometry based phenotyping, potency and killing assays, and in vivo using our established NOD/SCID/IL2Rgnull ovarian cancer xenograft mouse model.

The finalized culture, genetic engineering and cryopreservation process will be documented in an investigational medicinal product dossier (IMPD), which will be the basis for future phase I/IIa/IIb clinical trials using CAR-NK cells against OC.

Tasks and responsibilities

• Contribute to the development of new knowledge within the context of the department's research program.
• Design and perform scientific and immunomonitoring research.
• Write scientific publications and presents findings at scientific meetings.
• Work in a team with clinical and non-clinical PhD students, technicians and scientists.
• Discusse, plan and perform research in a stimulating environment.
• You are involved in NK cell culture in the GMP cleanroom facility.
• Write an investigational medicinal product dossier.
• Work in a highly international research group.