Due to their physiological role in removing damaged cells, natural killer (NK) cells represent ideal candidates for cellular immunotherapy in the treatment of cancer. Thereby, the cytotoxicity of NK ...cells is regulated by signals on both, the NK cells as well as the targeted tumor cells, and the interplay and balance of these signals determine the killing capacity of NK cells. One promising avenue in cancer treatment is therefore the combination of NK cell therapy with agents that either help to increase the killing capacity of NK cells or sensitize tumor cells to an NK cell-mediated attack. In this mini-review, we present different strategies that can be explored to unleash the potential of NK cell immunotherapy. In particular, we summarize how modulation of apoptosis signaling within tumor cells can be exploited to sensitize tumor cells to NK cell-mediated cytotoxicity.
Cellular therapy has entered the daily clinical life with the approval of CAR T cell therapeutics and dendritic cell (DCs) vaccines in the US and the EU. In addition, numerous other adoptive cellular ...products, including natural killer (NK) cells, are currently evaluated in early phase I/ II clinical trials for the treatment of cancer patients. Despite these promising accomplishments, various challenges remain to be mastered in order to ensure sustained therapeutic success. These include the identification of strategies by which tumor cells escape the immune system or establish an immunosuppressive tumor microenvironment (TME). As part of the innate immune system, DCs and NK cells are both present within the TME of various tumor entities. While NK cells are well known for their intrinsic anti-tumor activity by their cytotoxicity capacities and the secretion of pro-inflammatory cytokines, the role of DCs within the TME is a double-edged sword as different DC subsets have been described with either tumor-promoting or -inhibiting characteristics. In this review, we will discuss recent findings on the interaction of DCs and NK cells under physiological conditions and within the TME. One focus is the crosstalk of various DC subsets with NK cells and their impact on the progression or inhibition of tumor growth. In addition, we will provide suggestions to overcome the immunosuppressive outcome of the interaction of DCs and NK cells within the TME.
Anticoagulant therapy in pediatric patients remains an issue and safer therapies, such as direct oral anticoagulants could overcome the limitations of conventional anticoagulant treatments in this ...population. Edoxaban, a factor Xa inhibitor, is used for the prevention and treatment of venous thromboembolism. Due to its pharmacokinetic characteristics, edoxaban is a promising candidate molecule for children. This study compared edoxaban in vitro effect in children and adults.
Blood samples were prospectively collected from 87 adults and 97 children (n = 12: <2 year-old; n = 8: 2–4 year-old; n = 9: 5–7 year-old; n = 14: 8–9 year-old; n = 10: 10–13 year-old; n = 15: 14–15 year-old; and n = 29: 16–18 year-old). Plasma samples were supplemented in vitro with edoxaban to a final concentration of 50, 150 or 300 ng/mL, and then edoxaban effect on prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen (Clauss assay), specific anti-factor Xa activity and thrombin generation assay (TGA) (with 5pM tissue factor and 4 nM phospholipids) was evaluated.
PT, aPTT, and specific anti-Xa activity exhibited similar dose-dependent responses to edoxaban in the different age groups. The reduction of thrombin peak, the most edoxaban-sensitive TGA parameter, was similar in adults and children, but for the youngest group (<2 year-old) where the peak value reduction (median Q1–Q3) was higher than in adults (51% 44–59 versus 40% 32–46, p < 0.01; 74% 63–80 versus 65% 58–70, p < 0.05; and 84% 73–88 versus 76% 70–80, p < 0.05 for 50, 150 and 300 ng/mL edoxaban, respectively).
Edoxaban in vitro effect are comparable in children and adults except in the <2-year-old group.
•PT and aPTT exhibited similar dose-dependent responses to edoxaban regardless of age.•Thrombin generation is decreased in children under 8 years of age.•Edoxaban impact on thrombin generation was greater in child <2 year-age than adults.
Summary
Assessing minimal residual disease (MRD) in B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL) is essential for adjusting therapeutic strategies and predicting relapse. Quantitative ...polymerase chain reaction (qPCR) is the gold standard for MRD. Alternatively, flow cytometry is a quicker and cost‐effective method that typically uses leukaemia‐associated immunophenotype (LAIP) or different‐from‐normal (DFN) approaches for MRD assessment. This study describes an optimized 12‐colour flow cytometry antibody panel designed for BCP‐ALL diagnosis and MRD monitoring in a single tube. This method robustly differentiated hematogones and BCP‐ALL cells using two specific markers: CD43 and CD81. These and other markers (e.g. CD73, CD66c and CD49f) enhanced the specificity of BCP‐ALL cell detection. This innovative approach, based on a dual DFN/LAIP strategy with a principal component analysis method, can be used for all patients and enables MRD analysis even in the absence of a diagnostic sample. The robustness of our method for MRD monitoring was confirmed by the strong correlation (r = 0.87) with the qPCR results. Moreover, it simplifies and accelerates the preanalytical process through the use of a stain/lysis/wash method within a single tube (<2 h). Our flow cytometry‐based methodology improves the BCP‐ALL diagnosis efficiency and MRD management, offering a complementary method with considerable benefits for clinical laboratories.
This study presents an optimized 12‐colour flow cytometry panel for BCP‐ALL diagnosis and MRD monitoring, combining LAIP/DFN strategies with principal component analysis in a single tube. This approach enhances the specificity of differentiating hematogones and BCP‐ALL cells using specific markers: CD43 and CD81. Our method shows strong correlation with qPCR (r = 0.87) and simplifies the process (<2 h), offering a quicker, cost‐effective alternative for clinical labs.
Purpose
Childhood lymphoma survivors (CLSs) are at high risk of reduced daily activity. This work studied metabolic substrate use and cardiorespiratory function in response to exercise in CLSs.
...Methods
Twenty CLSs and 20 healthy adult controls matched for sex, age, and BMI took an incremental submaximal exercise test to determine fat/carbohydrate oxidation rates. Resting echocardiography and pulmonary functional tests were performed. Physical activity level, and blood metabolic and hormonal levels were measured.
Results
CLSs reported more physical activity than controls (6317 ± 3815 vs. 4268 ± 4354 MET-minutes/week,
p
= 0.013), had higher resting heart rate (83 ± 14 vs. 71 ± 13 bpm,
p
= 0.006), and showed altered global longitudinal strain (− 17.5 ± 2.1 vs. − 19.8 ± 1.6%,
p
= 0.003). We observed no difference in maximal fat oxidation between the groups, but it was reached at lower relative exercise intensities in CLSs (Fatmax 17.4 ± 6.0 vs. 20.1 ± 4.1 mL/kg,
p
= 0.021). At V̇O
2
peak, CLSs developed lower relative exercise power (3.2 ± 0.9 vs. 4.0 ± 0.7 W/kg,
p
= 0.012).
Conclusion
CLSs reported higher levels of physical activity but they attained maximal fat oxidation at lower relative oxygen uptake and applied lower relative power at V̇O
2
peak. CLSs may thus have lower muscular efficiency, causing greater fatigability in response to exercise, possibly related to chemotherapy exposure during adolescence and childhood. Long-term follow-up is essential and regular physical activity needs to be sustained.
Background
Myocardial work (MW) is a new echocardiographic tool with a high sensitivity to detect early and subtle alterations of myocardial function. We aimed to evaluate the late effects of ...anthracyclines by assessing the global and segmental MW and intraventricular mechanical dispersion from speckle tracking echocardiography in childhood lymphoma survivors (CLS).
Methods
Thirty‐one young adults including CLS and age‐matched healthy controls were enrolled. All underwent echocardiography including an evaluation of left ventricular (LV) morphology and regional function. We assessed LV longitudinal (differentiating sub‐endocardial and sub‐epicardial layers), circumferential strains and twist, global and regional MW index (MWI). LV mechanical dispersion was assessed from the time dispersion of LV longitudinal strain, from myocardial wasted work (MWW) and myocardial work efficiency (MWE).
Results
The longitudinal strains both at the level of the sub‐endocardium and sub‐epicardium were reduced in CLS compared to controls. The global MWI was also decreased (1668 ± 266 vs 1870 ± 264%.mmHg in CLS patients and controls, respectively, p < 0.05), especially on the apical segments. An increase of LV intraventricular mechanical dispersion was observed in CLS. MWW and MWE remained unchanged compared to controls.
Conclusion
Our results strongly support that cardiac remodeling is observed in CLS, characterized by a decrease in MW and an increase in LV mechanical dispersion. The apex is specifically altered, but its clinical significance remains uncertain. MW as a complement to strain seems interesting in cancer survivors to detect myocardial dysfunction at early stage and adapt their follow‐up.
Cardiac remodeling is observed in childhood lymphoma survivors, characterized by a modification in myocardial work and left ventricular mechanical dispersion. Myocardial work seems interesting in cancer survivors to detect myocardial dysfunction at an early stage and thus to adapt their follow‐up and management.
The induction of apoptosis is a direct way to eliminate tumor cells and improve cancer therapy. Apoptosis is tightly controlled by the balance of pro- and antiapoptotic Bcl-2 proteins. BH3 mimetics ...neutralize the antiapoptotic function of Bcl-2 proteins and are highly promising compounds inducing apoptosis in several cancer entities including pediatric malignancies. However, the clinical application of BH3 mimetics in solid tumors is impeded by the frequent resistance to single BH3 mimetics and the anticipated toxicity of high concentrations or combination treatments. One potential avenue to increase the potency of BH3 mimetics is the development of immune cell-based therapies to counteract the intrinsic apoptosis resistance of tumor cells and sensitize them to immune attack. Here, we describe spheroid cultures of pediatric cancer cells that can serve as models for drug testing. In these 3D models, we were able to demonstrate that activated allogeneic Natural Killer (NK) cells migrated into tumor spheroids and displayed cytotoxicity against a wide range of pediatric cancer spheroids, highlighting their potential as anti-tumor effector cells. Next, we investigated whether treatment of tumor spheroids with subtoxic concentrations of BH3 mimetics can increase the cytotoxicity of NK cells. Notably, the cytotoxic effects of NK cells were enhanced by the addition of BH3 mimetics. Treatment with either the Bcl-X
inhibitor A1331852 or the Mcl-1 inhibitor S63845 increased the cytotoxicity of NK cells and reduced spheroid size, while the Bcl-2 inhibitor ABT-199 had no effect on NK cell-mediated killing. Taken together, this is the first study to describe the combination of BH3 mimetics targeting Bcl-X
or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.
Hematopoietic progenitor cells‐apheresis (HPC‐A) collection is now a routine procedure for autologous hematopoietic stem cell transplantation. Here we present our 25 years' experience of HPC‐A ...collection in children weighing 8 kg or less, with a focus on the evolution of our standard operating procedures, and the safety limits for these young patients, in the Pediatric Apheresis Unit of Clermont‐Ferrand University Hospital (France). Fifteen children weighing 8 kg or less underwent 26 HPC‐A collections over 25 years. Median CD34+ cell yield by leukapheresis was 4.4 106/kg. No procedure‐related complications were encountered during or after the collection. No patient had profound thrombocytopenia or anemia that needed post‐collection transfusions. Our experience in pediatric oncology patients who underwent HPC‐A collections shows that this procedure can be performed even in the smallest of children with no increase in toxicity provided all precautions are taken to ensure that the procedure is carried out under the ideal conditions.
With the introduction of array comparative genomic hybridization (aCGH) techniques in the diagnostic setting of patients with developmental delay and congenital malformations, many new microdeletion ...syndromes have been recognized. One of these recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome, associated with variable clinical outcomes including developmental delay, autism spectrum disorder, epilepsy, and obesity, but also apparently normal phenotype. We report on a 16-year-old patient with developmental delay, exhibiting retinis pigmentosa with progressive visual failure from the age of 9 years, ataxia, and peripheral neuropathy. Chromosomal microarray analysis identified a 1.7-Mb 16p11.2 deletion encompassing the 593-kb common deletion (∼29.5 to ∼30.1 Mb; Hg18) and the 220-kb distal deletion (∼28.74 to ∼28.95 Mb; Hg18) that partially included the CLN3 gene. As the patient's clinical findings were different from usual 16p11.2 microdeletion phenotypes and showed some features reminiscent of juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, OMIM 204200), we suspected and confirmed a mutation of the remaining CLN3 allele. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletion represents one explanation for the phenotypic variability observed in chromosomal deletion disorders.
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