Single cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs

Single cell spatial interrogation of the immune-structural interactions in COVID −19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis

Caracterización de un nuevo antígeno de diferenciación distribuido clonalmente en células NK y linfocitos T "gama delta"

Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Mecicina, Departamento de Medicina. Fecha de lectura: 21 de Enero de 199

CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials

Bispecific antibody; Atezolizumab; Solid tumoursAnticuerpo biespecífico; Atezolizumab; Tumores sólidosAnticòs biespecífic; Atezolizumab; Tumors sòlidsCibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713). Primary endpoints were safety, dose finding, and pharmacokinetics in S1; safety and dose finding in S2. Secondary endpoints were anti-tumour activity (including overall response rate, ORR) and pharmacodynamics in S1; anti-tumour activity, pharmacodynamics and pharmacokinetics in S2. S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs). ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC

Selection of extreme phenotypes: the role of clinical observation in translational research NIH Public Access Author Manuscript

Abstract Systematic collection of phenotypes and their correlation with molecular data has been proposed as a useful method to advance in the study of disease. Although some databases for animal species are being developed, progress in humans is slow, probably due to the multifactorial origin of many human diseases and to the intricacy of accurately classifying phenotypes, among other factors. An alternative approach has been to identify and to study individuals or families with very characteristic, clinically relevant phenotypes. This strategy has shown increased efficiency to identify the molecular features underlying such phenotypes. While on most occasions the subjects selected for these studies presented harmful phenotypes, a few studies have been performed in individuals with very favourable phenotypes. The consistent results achieved suggest that it seems logical to further develop this strategy as a methodology to study human disease, including cancer. The identification and the study with high-throughput techniques of individuals showing a markedly decreased risk of developing cancer or of cancer patients presenting either an unusually favourable prognosis or striking responses following a specific treatment, might be promising ways to maximize the yield of this approach and to reveal the molecular causes that explain those phenotypes and thus highlight useful therapeutic targets. This manuscript reviews the current Correspondence to: José Luis Pérez-Gracia, [email protected]. Conflict of interest The authors declare that they have no conflict of interest relating to the publication of this manuscript. NIH Public Acces

El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones viráles crónicas

La manipulación farmacológica del sistema inmunitario para conseguir respuestas linfocitarias de mayor intensidad tiene aplicación potencial en inmunoterapia tumoral y en el tratamiento de enfermedades virales crónicas. Los anticuerpos monoclonales inmunoestimuladores se definen como una familia de fármacos que aumentan la respuesta inmunitaria al interaccionar como ligandos artificiales con proteínas funcionales del sistema inmunitario, activando o inhibiendo su función. Hay anticuerpos monoclonales humanizados dirigidos frente al receptor inhibidor linfocitario CD152 (CTLA-4) que se están probando en ensayos clínicos con evidencia de actividad antitumoral, aunque con la contrapartida de producir reacciones autoinmunitarias severas. Los anticuerpos anti-CD137 tienen la capacidad de inducir potentes respuestas inmunitarias, mediadas principalmente por linfocitos T citotóxicos, con el resultado de erradicar tumores transplantables de ratón de forma comparativamente superior a los anticuerpos frente a CD152. CD137 (4-1BB) es un antígeno de diferenciación expresado selectivamente en la superficie de linfocitos T y NK activados y sobre células dendríticas. Los anticuerpos monoclonales que actúan como ligandos artificiales estimuladores de este receptor (anticuerpos monoclonales agonistas anti-CD137) potencian la inmunidad celular antitumoral y antiviral en modelos experimentales murinos. Paradójicamente, estos mismos anticuerpos previenen o mejoran el curso de enfermedades autoinmunitarias establecidas en ratones como modelo. A la luz de estos datos experimentales, varios grupos de investigación han procedido a la humanización de anticuerpos dirigidos frente a CD137 humano y se plantea la inminente realización de los primeros ensayos clínicos

Whole exome sequencing and machine learning germline analysis of individuals presenting with phenotypes of extreme high and low risk of developing tobacco-induced lung adenocarcinoma

Background: Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at young age others never develop it, even at advanced age. This suggests a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML). Methods: We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at early age (extreme cases) or did not develop it at advanced age (extreme controls). The discovery and validation cohorts included respectively 50 and 66 extreme cases and 50 and 83 extreme controls, selected from databases including > 6,000 subjects. We selected individual coding variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We trained ML models (Logistic Regression, Random Forest, Support Vector machine Classifier (SVC)) on the discovery cohort to classify subjects into their respective phenotypes and tested them on the validation cohort. Results: Mean age for extreme cases and controls in both cohorts was 50.2 and 78.4 years. Mean tobacco consumption was 38.1 and 59.1 pack-years. We validated 16 significant individual variants. The most significant variants were in ADAMTS7 (2 variants) in cases and TMEM191B (1) in controls. We validated 33 genes enriched with significant variants. The genes harboring more variants were HLA-A (4 variants) and ADAMTS7 (2) in cases; and PLIN4 (2) in controls (Table). We trained several ML models on the discovery cohort using as input the 16 significant individual variants and the number of variants in the 33 enriched genes. We tested them in the validation cohort obtaining accuracy of 72% and AUC-ROC of 87.4% with the best model (SVC), using 16 variants as input, confirming their association with the phenotypes. Functions of validated genes included oncogenes, tumor-suppressors, DNA repair, maintenance of genomic stability, HLA mediated antigen presentation and regulation of proliferation, migration, apoptosis and inflammatory pathways. Conclusions: Individuals presenting phenotypes of extreme high and low risk of developing tobacco-induced lung adenocarcinoma have different germline profiles. Our strategy may allow to identify high-risk subjects and to develop new therapeutic approaches