Background
Recurrent pediatric medulloblastoma and ependymoma have a grim prognosis. We report a first-in-human, phase I study of intraventricular infusions of ex vivo expanded autologous natural killer (NK) cells in these tumors, with correlative studies.
Methods
Twelve patients were enrolled, 9 received protocol therapy up to 3 infusions weekly, in escalating doses from 3 × 106 to 3 × 108 NK cells/m2/infusion, for up to 3 cycles. Cerebrospinal fluid (CSF) was obtained for cellular profile, persistence, and phenotypic analysis of NK cells. Radiomic characterization on pretreatment MRI scans was performed in 7 patients, to develop a non-invasive imaging-based signature.
Results
Primary objectives of NK cell harvest, expansion, release, and safety of 112 intraventricular infusions of NK cells were achieved in all 9 patients. There were no dose-limiting toxicities. All patients showed progressive disease (PD), except 1 patient showed stable disease for one month at end of study follow-up. Another patient had transient radiographic response of the intraventricular tumor after 5 infusions of NK cell before progressing to PD. At higher dose levels, NK cells increased in the CSF during treatment with repetitive infusions (mean 11.6-fold). Frequent infusions of NK cells resulted in CSF pleocytosis. Radiomic signatures were profiled in 7 patients, evaluating ability to predict upfront radiographic changes, although they did not attain statistical significance.
Conclusions
This study demonstrated feasibility of production and safety of intraventricular infusions of autologous NK cells. These findings support further investigation of locoregional NK cell infusions in children with brain malignancies.
Purpose of review
To provide an update on risk factors associated with adenovirus (ADV) infection in patients after hematopoietic cell transplant (HCT) and on options for ADV monitoring and treatment in the setting of HCT.
Recent findings
Among patients undergoing HCT, ADV infection continues to be more common amongst those receiving a T-cell-depleted or graft other than from a matched-related donor. Among children undergoing HCT, reactivation in the gastrointestinal tract appears to be the most common source, and the virus is detectable by quantitative PCR in the stool before it is detectable in the blood. Thus, screening for the virus in the stool of these children may allow for preemptive therapy to reduce mortality. Brincidofovir, although still not approved by any regulatory agency, remains a potential agent for preemptive therapy and for salvage in cases not responding to cidofovir. Rapidly generated off-the-shelf virus-specific T cells may facilitate adoptive cell therapy in populations with a special need and previously not eligible for adoptive cell therapy, such as cord blood recipients.
Summary
ADV infection continues to adversely affect survival in HCT recipients. Screening stool in children and preemptive therapy may reduce mortality. Brincidofovir and adoptive T-cell therapy remain potential options for treatment.
BackgroundDespite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety.MethodsHere, for the first time reported in the literature, we have enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients as a possible marker of disease.ResultsWe constructed a ROC with an AUC of 0.831 resulting in a sensitivity of 85.3% and a specificity of 75%. Additionally, patients who were deemed to be CSV+ CTC positive were found to have a worse overall survival compared to those who were CSV+ CTC negative. We additionally found the use of available molecular testing increased the accuracy of our diagnostic and prognostic tests.ConclusionsOur findings indicate that CSV+ CTCs have prognostic value and can possibly serve as a measure of disease burden.
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