Phenotypic and functional characterization of mature dendritic cells from pediatric cancer patients

BACKGROUND: Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system. Clinical trials have demonstrated that mature DCs loaded with tumor-associated antigens can induce tumor-specific immune responses. Theoretically, pediatric patients are excellent candidates for immunotherapy since their immune system is more potent compared to adults. We studied whether sufficient amounts of mature monocyte-derived DCs can be cultured from peripheral blood of pediatric cancer patients. PROCEDURE: DCs from 15 pediatric patients with an untreated primary tumor were cultured from monocytes and matured with clinical grade cytokines. Phenotype and function were tested with flow cytometry, mixed lymphocyte reaction (MLR), and an in vitro migration assay. DCs of children with a solid tumor were compared with monocyte-derived DCs from age-related non-malignant controls. RESULTS: Ex vivo-generated monocyte-derived DCs from pediatric patients can be generated in numbers sufficient for DC vaccination trials. Upon cytokine stimulation the DCs highly upregulate the expression of the maturation markers CD80, CD83, and CD86. The mature DCs are six times more potent in inducing T cell proliferation compared to immature DCs. Furthermore, mature DCs, but not immature DCs, express the chemokine receptor CCR7 and have the capacity to migrate in vitro. CONCLUSIONS: These data indicate that mature DCs can be generated ex vivo to further optimize DC-vaccination trials in pediatric cancer patients.     

Data standards in pediatric oncology: Past,present, and future

In this commentary, we highlight the central role that data standards play in facilitating data-driven efforts to advance research in pediatric oncology. We discuss the current state of data standards for pediatric oncology and propose five steps to achieve an improved future state with benefits for clinicians, researchers, and patients.     

Pharmacokinetics and population pharmacokinetics in pediatric oncology

Pharmacokinetic research has become increasingly important in pediatric oncology as it can have direct clinical implications and is a crucial component in individualized medicine. Population pharmacokinetics has become a popular method especially in children, due to the potential for sparse sampling, flexible sampling times, computing of heterogeneous data, and identification of variability sources. However, population pharmacokinetic reports can be complex and difficult to interpret. The aim of this article is to provide a basic explanation of population pharmacokinetics, using clinical examples from the field of pediatric oncology, to facilitate the translation of pharmacokinetic research into the daily clinic.     

Management of febrile neutropenia in pediatric oncology patients: a Canadian survey

BACKGROUND: Traditionally, febrile neutropenia in pediatric oncology patients has been managed aggressively with hospital admission and intravenous antibiotics. Recent studies suggest that less intensive interventions are effective for selected children. Study of Canadian practice patterns may help better understand the current context of care for these patients. PROCEDURE: We carried out a cross-sectional mailed survey of the 17 tertiary pediatric centers in Canada. A 36-item questionnaire gathered information on oncology department characteristics, the existence of protocols for management of febrile neutropenia, use of outpatient therapy or early discharge, criteria used to identify patients at low risk, and opinions of oncologists. RESULTS: A total of 16 (94%) completed questionnaires were returned, reflecting a treatment population of approximately 2,100 children with febrile neutropenia/year. Three out of seventeen centers carry out exclusively traditional management. The remaining 14 offer modified treatment for low risk children. The majority (n = 10) carry out an early discharge approach. Two thirds of the episodes of febrile neutropenia are treated this way with good results. The rest (n = 4) implement complete outpatient management. Approximately 120 patients benefit from this annually, with a reportedly high success rate. Most specialists agreed on the benefits of decreased hospitalization for children with cancer. However, about half considered the level of evidence is not sufficient to fully implement complete outpatient management. CONCLUSIONS: Variations in the treatment of pediatric febrile neutropenia have been extensively implemented across Canada. However more evidence, ideally in the form of multicenter clinical trials, appears to be needed to further safely modify practice.     

Implementation of a formalized evaluation and planning tool to improve pediatric oncology outcomes in Kenya

Background

Survival from pediatric cancers in low middle-income countries is often very low compared to that of high-income countries due to multifactorial etiologies, including late presentation, delayed diagnosis, difficulty with accessing healthcare, drug unavailability, and treatment abandonment. The St. Jude Pediatric Oncology Facility Integrated Local Evaluation Tool (PrOFILE) was developed to map and evaluate childhood cancer healthcare delivery in individual institutions and entire countries, identifying the strengths and weaknesses, as well as opportunities for advancement of care.

Procedure

Using the PrOFILE self-assessment tool, selected Kenyan pediatric oncology facilities entered data into 12 modules: national context, facility and local context, finances and resources, personnel, service capacity, service integration, diagnostics, chemotherapy, supportive care, surgery, radiation therapy, and patients and outcomes. These modules are grouped into five specific components, including Context, Workforce, Diagnostics, Therapy, and Patients and Outcomes. The St. Jude PrOFILE team analyzed the data and organized the first hybrid workshop, containing both in-person and virtual components.

Results

Multidisciplinary stakeholders prioritized recommendations for improving care and developed smart objectives to accomplish identified goals over the following 2 years. Strengths and weaknesses of conducting a hybrid global workshop were identified.

Conclusions

We demonstrated successful use of the PrOFILE tool to conduct a hybrid workshop and identify strategies to improve pediatric oncology care in Kenya. The voluntarily structured work groups will methodically aim to achieve outcome-oriented goals moving forward.     

Medical marijuana in pediatric oncology: A review of the evidence and implications for practice

Medical marijuana (MM) has become increasingly legal at the state level and accessible to children with serious illness. Pediatric patients with cancer may be particularly receptive to MM, given purported benefits in managing cancer‐related symptoms. In this review, we examine the evidence for MM as a supportive care agent in pediatric oncology. We describe the current legal status of MM, mechanism of action, common formulations, and potential benefits versus risks for pediatric oncology patients. We offer suggestions for how providers might approach MM requests. Throughout, we comment on avenues for future investigation on this growing trend in supportive care.     

Programmed cell death ligand 1 (PD‐L1) expression is not a predominant feature in Ewing sarcomas

1 Background

Programmed cell death 1 (PD‐1) receptor engagement on T cells by its ligand programmed cell death ligand 1 (PD‐L1) is a key mechanism of immune escape, and antibody blockade of the interaction has emerged as an effective immunotherapeutic strategy in some cancers. The role and relevance of the PD‐1 checkpoint in Ewing sarcoma (EwS) is not yet understood.

2 Procedure

Here, we investigated expression of PD‐L1 and PD‐1 in EwS by immunohistochemistry analysis of pretherapeutic tumor biopsies and in tumor xenografts following treatment with human T cells engineered to express a chimeric antigen receptor (CAR) against the tumor‐associated antigen G_D2. PD‐L1 surface expression in EwS cell lines was assessed by flow cytometry.

3 Results

PD‐L1 expression was not detectable on tumor cells in any of the 60 EwS biopsies. Infiltrating PD‐L1 positive T cells were found in one tumor, and four biopsies contained PD‐1‐positive T cells. Of 13 EwS cell lines, none constitutively expressed PD‐L1 on the cell surface. Interferon‐γ cytokine stimulation induced upregulation of the ligand on all cell lines. Adoptive therapy with CAR gene‐modified T cells in a mouse model did not induce PD‐L1 expression in EwS xenografts despite tumor infiltration with PD‐1+ CD3+ T cells.

4 Conclusions

EwS cells can upregulate PD‐L1 under inflammatory conditions, but do not express the ligand in the pretherapeutic tumor microenvironment or postexposure to CAR T cells. PD‐1 checkpoint blockade alone is thus unlikely to evoke potent immune responses against EwS. Identification of the relevant immune evasion strategies in EwS will be vital for the development of effective immune targeting strategies.