Co-Stimulation Molecule Expression on Dendritic Cells in Children with Cancer – 2005

The following interim report from Elizabeth Algar was provided in the spring of 2005 and published in the CIKA Summer Newsletter that year.

How CIKA funds will contribute to the project:
This project will investigate the nature of the immunodeficiency that we have identified while performing phase one clinical trials using dendritic cell based immunotherapy in children with advanced malignancies. We will examine the expression and function of co-stimulation molecules on dendritic cells from cancer patients compared to the normal population. Dendritic cells are the initiators of the immune response and must stimulate T cells through two receptors coordinately (co-stimulation). Studying the co-stimulatory capacity of dendritic cells may provide help in explaining the immune deficiency that cancer patients display. The funds from CIKA will pay the salary for a research assistant and some consumables, both of which are necessary in order to perform the experiments that will enable us to answer these specific scientific questions with regard to improving understanding of the disease and treatments for children with cancer.

Results to date:
Overall we have now processed and analyzed 56fifty six samples for this study but still need more to achieve statistical significance across disease groups. This work shows promising results and with greater numbers we expect to be able to show significant findings.

Whole peripheral blood was collected prior to treatment for newly diagnosed children with cancer, either leukaemia or solid tumours and from healthy normal children. Red blood cells were lysed and remaining cells were stained with cell surface markers for dendritic cells (DC) and FlowCount beads added. Samples were analysed and DC numbers were accurately quantitated. It was found that cancer sufferers had, on average, less than half the absolute number of DC as compared to healthy children. Leukaemia patients returned lower numbers than patients with solid tumours.

Staff changes:
Gerlinda Amor resigned to work in the Cell Therapies Facility here at RCH and we have hired Sarah Fraser as her replacement. I also have a student from the Netherlands who is working on this project for six months as part of her medical training and therefore has come with her own funding, Jorinde Helmich.

Lastly I am going on maternity leave for twelve weeks beginning October 24, 2005. I will be fully contactable during this time and will be available in all respects for this work to proceed as described above.

A subsequent report:

Results to date:
Overall we have now processed and analysed 175 samples (80 since the last progress report) for this study and therefore have achieved our recruitment goals. This number of samples will allow us to be able to obtain statistical significance between disease groups (i.e., normals vs solid tumour group). Analysis of the data by disease groups shows that there is a significant difference in the number of DCs in children with newly diagnosed solid tumours and leukemia when compared to normal, healthy children. This is a novel finding and provides important information towards understanding the role of the immune function in children with cancer.

Additionally, we have investigated the quality of the DC in both normal children and in children with newly diagnosed cancer. We have shown statistically significant differences of expression of co-stimulatory molecules on the DCs. Importantly, of the ten molecules of interest examined not all show differences between the groups. Therefore the three molecules that show marked reductions in the children with cancer may point to particular defects in the immune function that we can then target for future therapeutics.

Additionally we have performed functional studies on the immune cells of these patients. We have found that, compared to normal children, children with newly diagnosed cancer have a significantly reduced ability to proliferate in response to a stimulus. This is a novel finding. Particularly, the impaired response in the solid tumour patient group has been of great interest, as their diseases do not involve the immune system per se. This work may have implications for future novel therapies.

In summary, we have collected a large amount of data on these newly diagnosed patient cohorts and are in the process of doing these analyses. We have completed the recruitment and experimental stages of this project. We anticipate being able to submit the manuscript for publication in a top peer reviewed journal within a few months.