Gerard M.J. Bos, MD, PhD
Maastricht University Medical Center
Abstract: Bone marrow stem cell transplantation is used in the treatment of patients with cancer, mostly hematological types of cancers. Both autologous transplants as well as allogeneic transplants can be used. Autologous transplantation is used to recover bone marrow after high dose chemotherapy with or without radiotherapy. Allogeneic transplantation is used to induce a graft versus tumor response against the patients’ malignant cells, based on an immunological mismatch between donor and recipient. Both treatments do induce a time period of immunosuppression in which the patient is at risk for infections. In autologous transplants, this risk is relatively low (mortality 2-5%). In allogeneic transplants, this risk is higher and partly depending on the source of the transplant that might lead to a state of immune-deficiency off over 3 months.
This clinical question led us to study the possible option of add back of T and/or Natural Killer (NK) cells cultured from stem cells in vitro. In vitro it is possible to culture (pre-) T cells from stem cells in the presence of feeder cells transfected with Notch-Ligands, that are crucial for T cell development. In order to test a feeder free system for GMP accredited clinical use, we observed that different media gave different results: the difference to be explained by the presence or absence of vitamin C. In the presence of Vitamin C double-positive T cells from stem cells can be obtained in the absence of stromal cells. However, for the further development to single positive T cells, stromal cells are still needed. In addition, we observed that also NK cells derived and matured faster from stem cells as well as from early pre T/NK cells in the presence of Vitamin C. These cells are completely functional NK cells.
Based on these in vitro data we went back to the clinic to see if patients that are treated for hematological diseases, with or without a stem cell transplantation, might have low vitamin C levels. Patients had lower Vitamin C levels (20.4 μM; N=42) compared to 65 μM in controls. 20% of the patients had levels below 11 μM or undetectable, considered to be Vitamin C deficient. In a more recent prospective study we do confirm this observation: patients do have lower vitamin C levels while on treatment compared to family members as controls.
These data are the basis for an intervention study using Vitamin C to see if leukocyte recovery and therefore infections, morbidity and mortality can be improved after stem-cell transplantation for hematological malignancies.