ABSTRACT
BACKGROUND: The field of cancer immunology is rapidly moving towards innovative therapeutic strategies, resulting in the need for robust and predictive preclinical platforms reflecting the immunological response to cancer. Well characterized preclinical models are essential for the development of predictive biomarkers in the oncology as well as the immune-oncology space. In the current study, gold standard preclinical models are being refined and combined with novel image analysis tools to meet those requirements. METHODS: A panel of 14 non-small cell lung cancer patient-derived xenograft models (NSCLC PDX) was propagated in humanized NOD/Shi-scid/IL-2Rnull mice. The models were comprehensively characterized for relevant phenotypic and molecular features, including flow cytometry, immunohistochemistry, histology, whole exome sequencing and cytokine secretion. RESULTS: Models reflecting hot (>5% tumor-infiltrating lymphocytes/TILs) as opposed to cold tumors (<5% TILs) significantly differed regarding their cytokine profiles, molecular genetic aberrations, stroma content, and programmed cell death ligand-1 status. Treatment experiments including anti cytotoxic T-lymphocyte-associated protein 4, anti-programmed cell death 1 or the combination thereof across all 14 models in the single mouse trial format showed distinctive tumor growth response and spatial immune cell patterns as monitored by computerized analysis of digitized whole-slide images. Image analysis provided for the first time qualitative evaluation of the extent to which PDX models retain the histological features from their original human donors. CONCLUSIONS: Deep phenotyping of PDX models in a humanized setting by combinations of computational pathology, immunohistochemistry, flow cytometry and proteomics enables the exhaustive analysis of innovative preclinical models and paves the way towards the development of translational biomarkers for immuno-oncology drugs.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Cytokines , Disease Models, Animal , Humans , Lung Neoplasms/drug therapy , Mice , Mice, Inbred NOD , Mice, SCIDABSTRACT
The concept of an artificial placenta has been pursued in experimental research since the early 1960s. The principle has yet to be successfully implemented in neonatal care despite the constant evolution in extracorporeal life support technology and advancements in neonatal intensive care in general. For more than three decades, the physical dimensions of the required equipment necessitated pump-driven circuits; however, recent advances in oxygenator technology have allowed exploration of the simpler and physiologically preferable concept of pumpless arteriovenous oxygenation. We expect that further miniaturization of the extracorporeal circuit will allow the implementation of the concept into clinical application as an assist device. To this end, NeonatOx (Fig. 1), a custom-made miniaturized oxygenator with a filling volume of 20 mL, designed by our own group, has been successfully implemented with a preterm lamb model of less than 2000 g body weight as an assist device. We provide an overview of milestones in the history of extracorporeal membrane oxygenation of the preterm newborn juxtaposed against current and future technological advancements. Key limitations, which need to be addressed in order to make mechanical gas exchange a clinical treatment option of prematurity-related lung failure, are also identified.
Subject(s)
Artificial Organs/history , Extracorporeal Membrane Oxygenation/history , Infant, Premature/physiology , Placenta/physiology , Animals , Catheterization/history , Extracorporeal Membrane Oxygenation/instrumentation , Extracorporeal Membrane Oxygenation/methods , Female , History, 20th Century , History, 21st Century , Humans , Infant, Newborn , PregnancySubject(s)
Choroid Diseases/diagnosis , Granuloma/diagnosis , Retinal Vasculitis/diagnosis , Sarcoidosis/diagnosis , Africa , Child , Choroid Diseases/drug therapy , Choroid Diseases/ethnology , Coloring Agents , Female , Fluorescein Angiography , Granuloma/drug therapy , Granuloma/ethnology , Humans , Immunosuppressive Agents/therapeutic use , Indocyanine Green , Male , Necrosis , Retinal Vasculitis/drug therapy , Retinal Vasculitis/ethnology , Sarcoidosis/drug therapy , Sarcoidosis/ethnologyABSTRACT
Gas exchange in premature neonates is regularly impaired by structural and functional immaturity of the lung. Mechanical ventilation, which is vitally important to sustain oxygenation and CO(2) elimination, causes, at the same time, mechanical and inflammatory destruction of lung tissue. To date, extracorporeal oxygenation is not a treatment option, one reason among others being the size of available oxygenators and cannulas. We hypothesized that a substantial improvement in gas exchange can be achieved by maintenance of the fetal cardiopulmonary bypass and interposition of a suitable passively driven (arteriovenous) membrane oxygenator. In close cooperation between engineers and neonatologists, we developed a miniaturized oxygenator and adapted cannulas to be used as a pumpless extracorporeal lung support that is connected to the circulation via cannulation of the umbilical cord vessels. First in vitro and in vivo studies show promising results. We regard this as one step on the way to clinical application of the artificial placenta.