Refine
Year of publication
- 2011 (2) (remove)
Document Type
- Article (2)
Language
- English (2)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
In an ongoing clinical phase I/II study, 16 pediatric patients suffering from high risk leukemia/tumors received highly purified donor natural killer (NK) cell immunotherapy (NK-DLI) at day (+3) +40 and +100 post haploidentical stem cell transplantation. However, literature about the influence of NK-DLI on recipient's immune system is scarce. Here we present concomitant results of a noninvasive in vivo monitoring approach of recipient's peripheral blood (PB) cells after transfer of either unstimulated (NK-DLI(unstim)) or IL-2 (1000 U/ml, 9–14 days) activated NK cells (NK-DLI(IL-2 stim)) along with their ex vivo secreted cytokine/chemokines. We performed phenotypical and functional characterizations of the NK-DLIs, detailed flow cytometric analyses of various PB cells and comprehensive cytokine/chemokine arrays before and after NK-DLI. Patients of both groups were comparable with regard to remission status, immune reconstitution, donor chimerism, KIR mismatching, stem cell and NK-DLI dose. Only after NK-DLI(IL-2 stim) was a rapid, almost complete loss of CD56(bright)CD16(dim/−) immune regulatory and CD56(dim)CD16(+) cytotoxic NK cells, monocytes, dendritic cells and eosinophils from PB circulation seen 10 min after infusion, while neutrophils significantly increased. The reduction of NK cells was due to both, a decrease in patients' own CD69(−) NCR(low)CD62L(+) NK cells as well as to a diminishing of the transferred cells from the NK-DLI(IL-2 stim) with the CD56(bright)CD16(+/−)CD69(+)NCR(high)CD62L(−) phenotype. All cell counts recovered within the next 24 h. Transfer of NK-DLI(IL-2 stim) translated into significantly increased levels of various cytokines/chemokines (i.e. IFN-γ, IL-6, MIP-1β) in patients' PB. Those remained stable for at least 1 h, presumably leading to endothelial activation, leukocyte adhesion and/or extravasation. In contrast, NK-DLI(unstim) did not cause any of the observed effects. In conclusion, we assume that the adoptive transfer of NK-DLI(IL-2 stim) under the influence of ex vivo and in vivo secreted cytokines/chemokines may promote NK cell trafficking and therefore might enhance efficacy of immunotherapy.
Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective.