BACKGROUND: Children and adolescents with primary multifocal, refractory or relapsed malignant extracranial solid tumors still have a poor prognosis inspite of intensive standard radio-/chemotherapy. Here complementary immunomodulatory treatment modalities may prove beneficial as consolidation therapy following cytoreduction. Neuroblastoma, Ewing tumor and soft tissue sarcoma cells have principally been shown to be susceptible towards both cytotoxic and humoral effector mechanisms. Yet in vivo they are not capable of inducing an effective antitumor response which has been attributed to low level MHC expression and lack of costimulatory surface molecules. Professional antigen - presenting cells such as dendritic cells (DCs) in contrast are capable of activating unprimed T cells and are therefore ideal tools for vaccine generation. RESULTS: Here we demonstrate that DCs may be generated from CD34+ progenitor cells to clinical scale in a three to four week cell culture process including an initial expansion and subsequent differentiation and maturation steps. DCs derived from CD34+ progenitors express the expected marker profile and are highly effective in stimulating allogeneic T cell effectors. We also demonstrate that they effectively take up fluorescence-labelled tumor cell lysate. DISCUSSION: Having established a cell culture process for clinical scale DC production utilizing CD34+ progenitors as the cellular source we discuss the role of CD34+ derived DCs in clinical vaccination protocols. The rationale for a phase I/II DC dose escalation study for high risk pediatric patients with extracranial solid tumors assessing safety, immunological and clinical efficacy of serial combined intranodal and subcutaneous injections of tumor cell lysate-pulsed autologous DCs is delineated.

Adolescent↗

PubMedDate not supplied

Similar survival following HLA-identical sibling transplantation for standard indication in children with haematologic malignancies: a single center comparison of mobilized peripheral blood stem cell with bone marrow transplantation.

BACKGROUND: Peripheral blood stem cell (PBSC) grafts are increasingly used for autologous and allogeneic haematopoietic stem cell transplantation (alloHSCT) with the aim to hasten neutrophil and platelet engraftment and thereby to reduce transplant-related complications due to infections, bleeding and graft failure. Based on the paucity of data on PBSC transplantation in children we performed a retrospective single-center analysis comparing the outcome of children receiving mobilized PBSC from human leukocyte antigen (HLA)-identical sibling donors to bone marrow (BM) transplant recipients. PATIENTS AND METHODS: Between 1996 and 2004, 16 children with haematologic malignancies and standard indication for alloHSCT underwent PBSC transplantation from HLA-identical sibling donors. The outcome of these children was compared to a historic control group of 19 bone marrow (BM) transplant recipients. Time to neutrophil engraftment, incidence of acute and chronic graft-versus-host disease (GvHD), relapse rate, transplant-related mortality, event-free and overall survival were analyzed. RESULTS: Neutrophil engraftment was achieved significantly faster after PBSC compared to BM transplantation with a median time to neutrophil engraftment of 11 (range: 8-21) and 19 (16-44) days for the PBSC and BM cohort, respectively (p < 0.001). Two of 19 (11 %) BM recipients did not achieve primary neutrophil engraftment and both patients died due to infectious complications. The rate of clinically significant acute GvHD > or = grade II was higher in the PBSC compared to the BM group (75 vs. 39 %; p = 0.045). Incidences of chronic GvHD (PBSC vs. BM: 60 vs. 44 %), death of disease (13 vs. 21 %) and death of complication (13 vs. 16 %) were comparable between both groups (p = ns). With a median follow up of 4.7 years (PBSC) and 10.2 years (BM) overall survival (PBSC vs. BM: 68.6 +/- 13.5 vs. 63.2 +/- 11.1 %; p = 0.65) and event-free survival (67.0 +/- 12.1 vs. 63.2 +/- 11.1 %; p = 0.80) is without demonstrable difference in both groups. CONCLUSIONS: Transplantation of PBSC compared to BM is associated with faster neutrophil engraftment and a higher rate of > or = grade II acute GvHD. As overall survival and event-free survival is similar when using PBSC and BM, PBSC is an alternative stem cell source for HLA-identical sibling transplantation. Further prospective analyses with higher number of patients stratified according to well established risk factors are required to define the precise role of both stem cell sources for children with haematologic malignancies.

Adolescent↗

PubMedDate not supplied

Identification of candidate target antigens for antibody-based immunotherapy in childhood B-cell precursor ALL.

BACKGROUND: Contemporary risk adapted treatment protocols for childhood acute lymphoblastic leukemia (ALL) rely on accurate risk assessment strategies for disease re-occurrence by incorporating clinical parameters as well as immunological, molecular and cytogenetic features of the blasts at initial manifestation. Additional risk stratification is provided by analysis of the IN VITRO and IN VIVO response of the blasts towards standard chemotherapy. Despite adapted therapies, a number of children with good and bad prognostic factors still fail therapy. One approach to this problem might be to incorporate monoclonal antibodies (MoAbs) as additional modalities into the first or second line treatment. PATIENTS AND METHODS: In order to identify target antigen structures, we analyzed the immunological expression profiles of blasts from 181 patients with B-cell precursor ALL treated at our institution in 11 years according to the CoALL-92/97/03 protocols. Blasts were classified according to the EGIL guidelines as 9 proB-, 110 common (c-) and 62 preB-ALL. RESULTS: > 99 and 96 % of patients expressed CD19 and CD22 on > 90 % of their blasts, respectively. HLA-DR on > 95 % blasts was present in all patients. CD10 was expressed on all c-/preB-ALL and absent on proB-ALL cells. CD20 was expressed on 11-37 % of B-cell precursor ALL samples. CD34 positive blasts were found in 89, 83 and 68 % of patients with proB-, c- and preB-ALL, respectively. CD37 expression was detected in 0-18 % of patients. < 20 % CD45(+) blasts were found in 11, 19 and 18 % of patients with proB-, c- and preB-ALL. CD33(+) was expressed on 33, 29 and 21 % of patients samples with proB-, c- and preB-ALL. Other myeloid antigens (CD13, CD14, CD15, CD65) were positive on blasts in < 25 % of patients. Analyses of the immunological profile of blasts in 9 consecutive children with relapse revealed that the antigen expression profile varied little compared to the initial diagnosis for CD10, CD19, CD22 and HLA-DR. CONCLUSIONS: These analyses clearly identified the three antigens CD19, CD22 and HLA-DR present on blasts in more than 90 % of patients as potential target structures for targeted therapies with native or toxin-bound monoclonal antibodies in childhood ALL.

Adolescent↗