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Effective T Cell Regeneration Following High-Dose Chemotherapy Rescued with CD34؉ Cell Enriched Peripheral Blood Progenitor Cells in Children

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Effective T Cell Regeneration Following High-Dose Chemotherapy Rescued with CD34؉ Cell Enriched Peripheral Blood Progenitor Cells in Children Bone Marrow Transplantation, (1999) 23, 347–353 1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt Effective T cell regeneration following high-dose chemotherapy rescued with CD34؉ cell enriched peripheral blood progenitor cells in children A Heitger1, H Kern1, D Mayerl1, K Maurer1, D Nachbaur2, M Fru¨hwirth1, F-M Fink1 and D Niederwieser3 1University Children’s Hospital Innsbruck; 2Department of Internal Medicine, Division of Clinical Immunobiology and Bone Marrow Transplantation, University Hospital Innsbruck, Austria; and 3Division Hematology and Oncology, University of Leipzig, Germany Summary: shown to be an effective treatment for high risk malig- nancies.1,2 Peripheral blood mononuclear cells (PBMC) that The ex vivo enrichment for the CD34؉ cell fraction of have been stimulated with G-CSF contain a small fraction PBPC, while it retains the capacity to restore haematopo- of haematopoietic CD34+ stem cells3,4 which are able suc- iesis and potentially reduces a contamination by tumour cessfully to restore haematopoiesis after myeloablative HD- cells, implements a depletion of T cells. To test whether CTX.5,6 The success of such treatment, however, may be such a setting adversely affects T cell reconstitution, we hampered by a contamination of the leukapheresis product monitored T cells in four paediatric patients after CD34؉ with residual circulating tumour cells.7–9 Therefore, the selected PBPC transplantation. The dose of CD34؉ cells, enrichment of G-CSF stimulated PBMC for CD34+ cells which were enriched to 74%, median, was 7.1 ؋ 106/kg, might be of benefit by reducing the risk of reinfusing vital median, that of T cells was 0.071 ؋ 106/kg, median. The tumour cells together with the leukapheresis product.10 This patients were homogenous with respect to features with a procedure, however, results in an effective depletion of T potential to effect T cell reconstitution (low median age, cells. Since previous evidence suggests that peripheral T (3.5 years); stage IV malignant tumours in first CR, cells reinfused together with bone marrow or PBPC sig- uncomplicated post-treatment course). The results of nificantly contribute to the reconstitution of T cells after sequential FACS analyses showed that by 9 months after myeloablative treatment,11–13 T cell depletion may treatment all four patients had recovered (1) a normal T adversely affect T cell regeneration.14 Recent reports of the cell count (CD3؉ cells 1434/␮l, median); (2) a normal kinetics of lymphoid reconstitution after CD34+ selected CD4؉ cell count (816/␮l, median), while CD8+ cells were autologous and allogeneic PBPC transplantation in children recovered (Ͼ330/␮l) already by 3 months; (3) a normal and adults15,16 showed that T cell reconstitution was CD4/CD8 ratio (1.8, median), as a result of an augmented delayed as compared to a rescue with unmanipulated grafts. growth of CD4؉ cells between 3 and 6 months (increase of We hypothesised that high residual thymic activity, as -CD4؉ cells 4.9-fold, median, CD8؉ cells 1.1-fold, median). present in early childhood, might allow for a rapid regener Expansion of cells with a CD45RA؉ phenotype (thymus- ation of T cells in the absence of suppressive factors, such derived T cells) predominated; from 3 to 6 months the as GVHD, and studied T cell regeneration in four paediatric -increase of CD4؉/CD45RA؉ T cells was 130-fold, that of patients after autologous CD34+ selected PBPC transplan CD4؉/CD45RO؉ cells was 1.7-fold; CD8؉/CD45RA؉ cells tation. These patients were most homogenous with respect -increased 9-fold, CD8؉/CD45RO؉ cells increased 2.1-fold, to factors with a potential relevance to the T cell regenerat indicating effective thymopoiesis. The findings demon- ive capacity (see below). The results show an effective and strate that in paediatric patients the setting of HD-CTX rapid reconstitution of T cells and T cell subsets based on rescued with autologous CD34؉ selected PBPC per se is a preferential use of a thymopoietic pathway, indicating that not predictive of an impaired T cell recovery. High thymic T cell depletion of PBPC by positive selection for CD34+ activity may be a key factor for the rapid restoration of cells does not per se adversely affect T cell reconstitution T cells. in the paediatric age group. Keywords: CD34+ enrichment; peripheral stem cell res- cue; T cell reconstitution; children; solid tumours Patients and methods High-dose chemotherapy (HD-CTX) with autologous per- Patients ipheral blood progenitor cell (PBPC) rescue has been The clinical characteristics of the patients are summarised in Table 1. Care was taken to avoid a variety of combi- Correspondence: Dr A Heitger, University Children’s Hospital, Anich- nations of factors with a potential relevance to T cell regen- stra␤e 35, A-6020 Innsbruck, Austria erative capacity. The four consecutively treated patients had Received 3 August 1998; accepted 21 September 1998 similar clinical features. The median age was low (3.5 CD34؉ enriched PBPC rescue and T cell recovery in children A Heitger et al 348 Table 1 Patient characteristics Patient sex, Diagnosis Preparative CD34+ cells T cells Engraftment Outcome age (years) regimen reinfused reinfused (WBC (time after (×106/kg) (×106/kg) Ͼ1.0 ϫ 109/l) reinfusion of stem cells) 1 M, 3 neuroblastoma IV MEC 7.6 0.16 +11 alive, well (4 yrs 4 mo) 2 M, 2 neuroblastoma IV MEC 9.5 0.057 +12 alive, well (1 yr 11 mo) 3 M, 4 rhabdomyosarcoma IV MEC 6.6 ND +12 alive, well (1 yr 10 mo) 4 F, 8 neuroblastoma IV MEC 1.9 0.071 +13 dead of relapse (1 yr 6 mo) m = male; f = female; yrs = years; mo = months; MEC = melphalan 160 mg/m2 in patients 1, 2; 140 mg/m2 in patients 3, 4; etoposide 60 mg/kg; carboplati- num 1500 mg/m2;ND= not determined. years, range 2–8 years). All had advanced stage malignant number of reinfused T cells ranged from 0.057 to tumours, all had been treated with four to six courses of 0.16 × 106/kg (Table 1). conventional chemotherapy and were in first CR prior to receiving autologous PBPC rescue, and received the same Analysis of T cell regeneration preparative regimen. The engraftment was supported by rh- G-CSF (5–10 ␮g/kg/day s.c.) and was rapid and stable in T cells and T cell subsets were quantified by FACS. The all four cases. With respect to the post-transplant period following fluorochrome-labeled monoclonal antibodies none of the patients received extended field radiation ther- (MoAb), all purchased from Becton Dickinson (BD; Moun- apy and all patients had an uncomplicated post-transplant tain View, CA, USA), were used: negative controls, Simult- course, ie no severe infection, no evidence of a tumour est control (fluorescein (FITC), phycoerythrin (PE)), IgG1 relapse, while being investigated for T cell reconstitution. (peridinin chlorophyll protein (PerCP)); anti-CD3 (PerCP); anti-CD4 (PerCP or FITC); anti-CD8 (PerCP or PE); anti- ␣␤ Composition of CD34+ selected PBPC CD45RA (FITC); anti-CD45RO (PE); anti-TCR (FITC); anti-TCR␥␦ (FITC). To quantify a contamination with red The methods of collection and selection of CD34+ cells blood cells one portion of each sample was also stained have recently been described.17 Briefly, PBMC were with anti-glycophorin A (PE). Peripheral heparinized blood collected in the phase of haematopoietic recovery after was collected on the occasion of regular follow-up visits cytotoxic treatment and stimulation with rh-G-CSF with informed consent of the parents from 3 to 12 months (5 ␮g/kg/day). PBMC were separated from whole blood after treatment (missing examinations: patient No. 1 at 9 using a CS 3000 Plus cell separator (Baxter, Healthcare months for technical reasons, patient No. 4 at 12 months Fenwal Division, Deerfield, IL, USA). Three leukaphereses because of relapse with haematopoietic failure due to bone were performed on each patient. The PBMC of the first two marrow infiltration by tumour cells). PBMC were isolated leukapheresis products were pooled and CD34+ cells were from whole blood by Lymphoprep (Nycomed, Oslo, positively selected on a Ceprate SC Stem Cell Concen- Norway) density centrifugation and washed twice. The tration System loaded with a CD34-specific biotinylated isolated PBMC population usually contained less than 2% monoclonal antibody (CellPro, Bothell, WA, USA). This glycophorin A+ cells. Aliquots of 300 000 cells were first resulted in an enrichment for CD34+ cells of 74%, median incubated with MOPC 21 (mouse IgG1 ␬; Sigma, St Louis, (range 51–88%). Before use the cells were cryopreserved MO, USA) on ice for 20 min to block non-specific binding. in 10% DMSO by controlled rate freezing and stored in Then the cells were stained with the appropriate MoAb by liquid nitrogen. The third apheresis product was cryopre- incubation on ice for 30 min, washed twice and immedi- served as a back-up. ately analysed on a FACScan flow cytometer (BD). Lym- With respect to T cells, conventional chemotherapy for phocytes were identified by forward scatter (FSC) vs side neuroblastoma and rhabdomyosarcoma, as given to these scatter (SSC) and gated electronically to allow for a calcu- patients, invariably induces a severe depletion of T cells lation of absolute cell numbers (see below). (Ref. 18 and manuscript in preparation). For example, The analyses of two- and three-colour studies were per- patient No. 1 had only 68/␮l CD3+ cells 3 weeks prior to formed on a FACScan research software 2.1 (BD). Three- HD-CTX with CD4+/45RA+ cells being most severely colour analysis was performed to examine T cell subsets depleted. These abnormalities of T cells translated into the within a preselected T cell population, as described.20 To apheresis product.
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