Current available animal and in vitro cell-based models for studying brain-related pathologies and drug evaluation face several limitations since they are unable to reproduce the unique architecture and physiology of the human blood–brain barrier. Because of that, promising preclinical drug candidates often fail in clinical trials due to their inability to penetrate the blood–brain barrier (BBB). Therefore, novel models that allow us to successfully predict drug permeability through the BBB would accelerate the implementation of much-needed therapies for glioblastoma, Alzheimer’s disease, and further disorders. In line with this, organ-on-chip models of the BBB are an interesting alternative to traditional models. These microfluidic models provide the necessary support to recreate the architecture of the BBB and mimic the fluidic conditions of the cerebral microvasculature. Herein, the most recent advances in organ-on-chip models for the BBB are reviewed, focusing on their potential to provide robust and reliable data regarding drug candidate ability to reach the brain parenchyma. We point out recent achievements and challenges to overcome in order to advance in more biomimetic in vitro experimental models based on OOO technology. The minimum requirements that should be met to be considered biomimetic (cellular types, fluid flow, and tissular architecture), and consequently, a solid alternative to in vitro traditional models or animals.

Background: Adoptive cell therapies are emerging as a promising therapeutic option against hematological and solid malignancies. Memory-like natural killer (mlNK) cells are a specific subtype of NK cells generated after cytokine preactivation that have shown enhanced in vivo persistence after infusion into patients, an issue that has hindered traditional NK cell immunotherapy. However, the quality and variability of mlNK cell products remains poorly defined. Methods: In this study, we evaluated heterogeneity across critical functional and molecular aspects of mlNK cells generated from independent donors, including mlNK cytotoxicity, cluster formation, motility, mitochondria morphology, and gene expression. Results: We observed a correlation between changes in gene expression associated with glycolysis and key NK cell functions such as cytotoxicity and motility. For further characterization, we blocked glycolysis and oxidative phosphorylation (OXPHOS) and observed an impaired mlNK functional response, suggesting the importance of metabolism. Conclusions: Our findings provide insights into discriminating between mlNK cell products and how the predictive markers can identify optimal mlNK cell products for adoptive cell therapy of cancer.

CtDNA is evolving as an important biomarker for ICI treatment response assessment in advanced melanoma. However, the utility of ctDNA monitoring during concurrent ICI with RT remains incompletely explored. In this multicenter, retrospective study, patients with unresectable stage III/IV melanoma treated with ICI and palliative RT were identified. Patients had retrospectively collected, tumor-informed, exome-based, ctDNA monitoring within 3 months following RT. 50 patients treated with ICI and palliative RT were analyzed. Patients with ctDNA clearance had significantly longer OS (HR 2.10, 95% CI 1.16-3.80, p=0.014) compared to those with increasing or decreasing and detectable ctDNA following RT. One-year OS was 85.9% with ctDNA clearance, 30.6% with decreasing ctDNA, and 22.0% for increasing ctDNA. In a multivariable analysis, both decreasing and increasing ctDNA were associated with worse OS compared with ctDNA clearance (HR 5.08 [95% CI, 1.26–20.48, p=0.022] and HR 9.83 [95% CI, 2.69–35.94, p< 0.001], respectively). Among patients with advanced melanoma treated with ICI and palliative RT, ctDNA clearance is associated with significantly improved OS compared to patients with detectable ctDNA within 3 months following RT. Ongoing studies are needed to understand the role of ctDNA in this population.

Background/Objectives: ctDNA is evolving as an important biomarker for prognostic assessment in advanced melanoma. However, the utility of ctDNA monitoring during concurrent ICI with RT remains incompletely explored. Methods: In this multicenter retrospective study, patients with unresectable stage III/IV melanoma treated with ICI and palliative RT were identified. Patients had retrospectively collected, tumor-informed, exome-based, ctDNA monitoring within 3 months following RT. Results: A total of 50 patients treated with ICI and palliative RT were analyzed. Compared with ctDNA clearance, ctDNA detectable and increasing was associated with worse OS (adjusted HR 2.52, 95% CI 1.20–5.29; p = 0.015), whereas ctDNA detectable and decreasing was not significantly different from ctDNA clearance (adjusted HR 1.58, 95% CI 0.69–3.65; p = 0.282). One-year OS was 87.5% with persistently undetectable ctDNA, 83.3% for ctDNA clearance, 46.3% for detectable and decreasing ctDNA, and 21.4% for detectable and increasing ctDNA. In a multivariable analysis, detectable and increasing ctDNA was associated with worse OS compared with ctDNA clearance (HR 2.52, 95% CI, 1.20–5.29, p = 0.015). Conclusions: Among patients with advanced melanoma treated with ICI and palliative RT, ctDNA clearance is associated with significantly improved OS compared to patients with detectable and increasing ctDNA within 3 months following RT. Ongoing prospective studies are needed to understand the role of ctDNA in this population.