Human adenovirus (HAdV) infections are increasingly recognized as important pathogens in immunocompromised hosts, especially in patients with severely suppressed T‐cell function. The 4th European ...Conference of Infections in Leukemia (ECIL‐4) has developed evidence‐based guidelines for diagnosis and management of HAdV infections. The risk for HAdV‐associated disease is increased in children, and risk factors for HAdV disease are T‐cell depletion, unrelated and cord blood hematopoietic stem cell transplantation, graft‐versus‐host disease grades III–IV, and lymphopenia. The recommended technique for monitoring of high‐risk patients is quantitative polymerase chain reaction. Cidofovir is the most used antiviral therapy, although no controlled study has been performed. HAdV‐specific T‐cell therapy is in development.
Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received αβ T- and B-cell-depleted allografts from ...haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCRαβ and anti-CD19 Abs and immunomagnetic microbeads. The γδ T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/μL, >200 CD19+ cells/μL and >200 CD56+ cells/μL for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/μL), for CD3+4+ at day +30 (58 vs 11 cells/μL) and for CD56+ at day +14 (622 vs 27 cells/μL). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.
Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received alpha beta T- and B-cell-depleted ...allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCR alpha beta and anti-CD19 Abs and immunomagnetic microbeads. The gamma delta T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/ mu L, >200 CD19+ cells/ mu L and >200 CD56+ cells/ mu L for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/ mu L), for CD3+4+ at day +30 (58 vs 11 cells/ mu L) and for CD56+ at day +14 (622 vs 27 cells/ mu L). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.
Bone marrow metastases-noted in 6% of patients with rhabdomyosarcoma-have been linked to very poor outcomes. Bilateral bone marrow sampling from iliac crests has been the gold standard for bone ...marrow examination in rhabdomyosarcoma, but sampling errors due to patchy bone marrow involvement may limit its sensitivity. Here, we report the case of a 6-year-old boy with embryonal rhabdomyosarcoma of the skull base and multiple 2-
Ffluoro-2-deoxy-D-glucose (2-
FFDG)-avid bone marrow metastases visualized by positron emission tomography and computed tomography (2-
FFDG PET/CT). His bone marrow aspirates were tumor-free. This case illustrates the diagnostic value of 2-
FFDG PET/CT in the detection of bone marrow metastases in rhabdomyosarcoma patients, which may re-shape the definition of bone marrow disease and, ultimately, alter disease staging and risk stratification.
Background & AimAutologous MNC apheresis is applied for the preparation of various advanced therapy medicinal products (ATMPs) for immunotherapy of cancer. The recruitment of cells during ...leukapheresis results in unexpectedly high yields in some patients. It is further characterized by an algorithm for calculation of CD34+ HPC yield in stem cell collection (see: Humpe et al, Transfusion 2000; 40: 1363-70).Methods, Results & ConclusionMethods 9 patients were subjected to autologous MNC leukapheresis procedures on a cell separator (Spectra Optia, V11.0, CMNC programme, TerumoBCT). Blood counts and quantification of lymphocyte subpopulations were done before and after leukapheresis as well as in the apheresis product on a hematology analyzer (Sysmex K21) and a flow cytometer (FACS Verse, BD). From the results and the apheresis key data cell yields, collection efficiency (CE2) and recruitment as well as the predicted yields by the above mentioned algorithm were calculated.ResultsThe yields in 9 procedures averaged to vital TNC s 1.4*10E10, monocytes (MC) 3.8 *10E9, lymphocytes (LY) 6.7*10E9, CD3+ T cells (TC) 5.5 *10E9, NK cells (NKs) 11.5*10E8, platelets (PLT) 23.3 *10E10, respectively. Though CD34+ HPCs in the blood of 6/9 patients were below 1/µl, they were detected in all apheresis products (average 4.4*10E7 CD34+ HPCs). CE2 was independent of counts in peripheral blood and amounted to 0.61 for MC, 0.65 for LY and TC, respectively, 0.60 for NKs and 0.11 for PLT. In the model for the prediction of CD34+ HPC yields decribed by Humpe et al, the calculated amounts overestimated PLT yields (4.5fold), but underscored the harvests of NK, TC and MC 0.5fold, 0.4fold and 0.6fold, respectively. Predicted and measured cell contents were highly correlated as for NK and PLT (R 2 >0.8), moderately for MC and TC (R 2∼0.6). Only with TC, a significant, but negative correlation was found between the percentage of cells recruited into the product and the ratio of predicted to recorded yield. Despite a high interindividual variance, the portion of cells recruited into the product were similar for MC, LY, TC and NK (0.41, 0.46, 0.48, 0.37), except for PLT (-2.10). ConclusionYields in MNC leukapheresis cannot be predicted using the same algorithm as in CD34+ HPC collection. We speculate that this is due to a considerable recruitment of cells into the apheresis product, resulting in unexpectedly high yields despite low blood counts. Hence, an apheresis collection may serve as liquid biopsy.
To evaluate the human herpes virus 6 (HHV-6) -specific immune response in individuals with chromosomally integrated HHV-6 (ciHHV-6), we measured HHV-6-antigen-specific cytokine responses ...(interferon-γ, interleukin-2, tumour necrosis factor-α) in T cells by flow cytometry in 12 and 16 individuals with and without ciHHV-6, respectively. All individuals with ciHHV-6 showed HHV-6-specific T cells with higher frequencies of HHV-6-specific CD8+ cells (0.03–14.93, median 2.15% of CD8+ cells) compared with non-ciHHV-6 (0.0–10.67, median 0.36%, p 0.026). The observed increased HHV-6-specific functionally active responses in individuals with ciHHV-6 clearly disprove speculations on immune tolerance in ciHHV-6 and indicate clinical and immunological implications of ciHHV-6.
Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one ...peak in young adolescents and another in patients 55-59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5-10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-ß as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4 Gy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.
Purpose
In 2014, we published the qPET method to quantify fluorodeoxyglucose positron emission tomography (FDG‐PET) responses. Analysis of the distribution of the quantified signals suggested that a ...clearly abnormal FDG‐PET response corresponds to a visual Deauville score (vDS) of 5 and high qPET values ≥ 2. Evaluation in long‐term outcome data is still pending. Therefore, we analyzed progression‐free survival (PFS) by early FDG‐PET response in a subset of the GPOH‐HD2002 trial for pediatric Hodgkin lymphoma (PHL).
Patients/Methods
Pairwise FDG‐PET scans for initial staging and early response assessment after two cycles of chemotherapy were available in 93 PHL patients. vDS and qPET measurement were performed and related to PFS.
Results
Patients with a qPET value ≥ 2.0 or vDS of 5 had 5‐year PFS rates of 44%, respectively 50%. Those with qPET values < 2.0 or vDS 1 to 4 had 5‐year PFS rates of 90%, respectively 80%. The positive predictive value of FDG‐PET response assessment increased from 18% (9%; 33%) using a qPET threshold of 0.95 (vDS ≤ 3) to 30% (13%; 54%) for a qPET threshold of 1.3 (vDS ≤ 4) and to 56% (23%; 85%) when the qPET threshold was ≥ 2.0 (vDS 5). The negative predictive values remained stable at ≥92% (CI: 82%; 98%).
Conclusion
Only strongly enhanced residual FDG uptake in early response PET (vDS 5 or qPET ≥ 2, respectively) seems to be markedly prognostic in PHL when treatment according to the GPOH‐HD‐2002 protocol is given.
BackgroundThe majority of solid tumors in pediatric patients occurs in the central nervous system, with medulloblastoma accounting for approximately 20% of pediatric brain tumors. Current treatment, ...involving resection, radiotherapy, and chemotherapy, improves long-term survival but is associated with significant adverse effects. Hence, there is an urgent need for novel therapeutic approaches. Chimeric Antigen Receptor (CAR) T-cell therapy has shown promise in treating hematologic malignancies. Its potential suitability for medulloblastoma remains uncertain. Initial preclinical and clinical studies suggest efficacy, but the dynamics of CAR-T recruitment, their interactions with tumor cells, optimal administration routes (intravenous, intraventricular, intratumoral), and mechanisms of potential treatment failure are unclear. To address these gaps, we aimed to establish an in vivo model for further investigation of CAR T-treatment in medulloblastoma.Materials and MethodsThree weeks after the microsurgical implantation of a chronic cerebellar window in immunodeficient FoxN1 mice, red fluorescent human medulloblastoma cells (DAOYtdt; SHH) were injected into the cerebellum. After 20 days solid tumor had formed, and CAR T-cellsGFP directed against the surface antigen B7-H3 were injected at a distance of 1mm adjacent to the tumor. As control, we used antiCD-19 CAR T-cellsGFP. Intravital two-photon laser scanning microscopy was used to longitudinally monitor tumor growth and CAR T-cells at a cellular level.ResultsWe successfully established a xenogeneic orthotopic medulloblastoma model which allows repetitive in vivo microscopy on a cellular resolution. Our preliminary results show, that following intracranial injection CAR T-cells were recruited to the tumor site and reduced tumor growth.ConclusionsOur mouse model can be used to evaluate the efficacy of CAR T-treatment for medulloblastoma and analyze CAR T-biology at a cellular level. Preliminary data showed a possible efficacy of antiB7-H3 CARs. In further experiments, we plan to dissect the efficacy of different application routes on the treatment efficacy. J.J. Herold: None. N. Teske: None. N.N. Kutlu: None. L. Dengler: None. C. Eberle: None. E. Nikolaishvili: None. P. Karschnia: None. J. Blobner: None. K. Müller: None. S. Langer: None. V. Buschinger: None. L. Warmuth: None. D.H. Busch: None. V.R. Buchholz: None. N. Thon: None. J.C. Tonn: None. T. Feuchtinger: None. L. von Baumgarten: None.
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