SUMMARY
Developing an immunotherapy treatment requires generating NK cells, which will work in the patient as an “army of rescuers”. Many variables have to be tested: donors, kinds of cells that are separated from the blood, substances to improve the activity of the cells, conditions in which the cells will be processed. Furthermore, each cancer is different, and these variables must be tested in cells and laboratory mice before being applied to persons. The team purports to establish the necessary conditions and procedures for the successful treatment of children.
OVERVIEW
We propose a new and ambitious research project with the aim of creating a team of medical and research professionals to develop cell therapies with Natural Killer lymphocytes (“NK cell team”) in children with cancer who cannot be cured with the usual treatment schemes.
Most childhood tumours can be eliminated by Natural Killer (NK) cells. However, children with refractory cancer present qualitative and functional alterations in their NK cells that favour tumour progression.
NK cells are lymphocytes of our innate immune system, whose main function is defence against tumours and infections. This feature is regulated by a complex recognition system between receptor, activator and inhibitor NKs, with their ligands in the tumour cells, mainly major histocompatibility complex class-I molecules (HLA-I) and variants (MICA/B).
This NK receptor-tumour ligand interaction constitutes the biological basis of anti-tumour recognition, and our understanding of it allows us to develop anti-tumour immunological strategies that revert the immune tolerance state of the patient. In this context, the principal investigator of this project is currently developing a clinical trial in a paediatric population with cancer using the allogenic transplant of hematopoietic parents of haploidentical donor as a platform to exploit the anti-tumour effect of NK cells.
The objective of this project is the creation of an “NK cell team” to be able to identify:
- In the patient: the characteristics and functionality of the NK cells.
- In the tumour: the capability of being eliminated by NK cells.
- Establishing tailored immune system management strategies with NK cells to increase the vulnerability of the cancer to the cell therapy through an in vivo xenotransplantation model.
OBJECTIVES
To create and develop an “NK cell team” comprising at least one technician and/or pre-doctoral intern to support the NK cell therapy projects in paediatric patients, to be able to identify:
- In the patient: the genomic, proteomic and functional profile of their NK cells at diagnosis.
- In the tumour: the genomic and proteomic profile of the ligands for NK cells.
- In the NK tumour cross-talk: the anti-tumour effect of the patient’s NK cells and its manipulation with healthy donors’ NKs, with or without stimulation, in the evolution of the tumour using a xenotransplantation animal model.
With administration of NK cells to the patient, to carry out studies with:
- Nano-particles which allow the guidance of the NK cells to the tumour.
- Chimeric antigen receptors in the NK cells (CARs) which improve the specific interaction with the tumour cell and make the attack more effective.
RESULTS
To date, different methods have been tested to obtain the activated and expanded NK cells, with different activating substances such as IL-15, analysing the quantity of T-cells contained in the extract, they have been characterised by their receptors or antigens and their effectiveness in the fight against the tumours studied. In this way, the ideal strategy has been determined for the treatment of children in subsequent trials.
Studies with nano-particles are also in progress in order to optimise the contact between the NK cells and the tumour cells.