Description: Background Despite a concerted policy effort in Europe, social inequalities in health are a persistent problem. Developing a standardised measure of socioeconomic level across Europe will improve the understanding of the underlying mechanisms and causes of inequalities. This will facilitate developing, implementing and assessing new and more effective policies, and will improve the comparability and reproducibility of health inequality studies among countries. This paper presents the extension of the European Deprivation Index (EDI), a standardised measure first developed in France, to four other European countries—Italy, Portugal, Spain and England, using available 2001 and 1999 national census data. Methods and results The method previously tested and validated to construct the French EDI was used: first, an individual indicator for relative deprivation was constructed, defined by the minimal number of unmet fundamental needs associated with both objective (income) poverty and subjective poverty. Second, variables available at both individual (European survey) and aggregate (census) levels were identified. Third, an ecological deprivation index was constructed by selecting the set of weighted variables from the second step that best correlated with the individual deprivation indicator. Conclusions For each country, the EDI is a weighted combination of aggregated variables from the national census that are most highly correlated with a country-specific individual deprivation indicator. This tool will improve both the historical and international comparability of studies, our understanding of the mechanisms underlying social inequalities in health and implementation of intervention to tackle social inequalities in health.

Description: B lymphocytes are a key pathologic feature of multiple sclerosis (MS) and are becoming an important therapeutic target for this condition. Currently, there is no approved technique to noninvasively visualize B cells in the central nervous system (CNS) to monitor MS disease progression and response to therapies. Here, we evaluated 64 Cu-rituximab, a radiolabeled antibody specifically targeting the human B cell marker CD20, for its ability to image B cells in a mouse model of MS using PET. Methods: To model CNS infiltration by B cells, experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice that express human CD20 on B cells. EAE mice were given subcutaneous injections of myelin oligodendrocyte glycoprotein fragment 1–125 emulsified in complete Freund adjuvant. Control mice received complete Freund adjuvant alone. PET imaging of EAE and control mice was performed 1, 4, and 19 h after 64 Cu-rituximab administration. Mice were perfused and sacrificed after the final PET scan, and radioactivity in dissected tissues was measured with a -counter. CNS tissues from these mice were immunostained to quantify B cells or were further analyzed via digital autoradiography. Results: Lumbar spinal cord PET signal was significantly higher in EAE mice than in controls at all evaluated time points (e.g., 1 h after injection: 5.44 ± 0.37 vs. 3.33 ± 0.20 percentage injected dose [%ID]/g, P 〈 0.05). 64 Cu-rituximab PET signal in brain regions ranged between 1.74 ± 0.11 and 2.93 ± 0.15 %ID/g for EAE mice, compared with 1.25 ± 0.08 and 2.24 ± 0.11 %ID/g for controls ( P 〈 0.05 for all regions except striatum and thalamus at 1 h after injection). Similarly, ex vivo biodistribution results revealed notably higher 64 Cu-rituximab uptake in the brain and spinal cord of huCD20tg EAE, and B220 immunostaining verified that increased 64 Cu-rituximab uptake in CNS tissues corresponded with elevated B cells. Conclusion: B cells can be detected in the CNS of EAE mice using 64 Cu-rituximab PET. Results from these studies warrant further investigation of 64 Cu-rituximab in EAE models and consideration of use in MS patients to evaluate its potential for detecting and monitoring B cells in the progression and treatment of this disease. These results represent an initial step toward generating a platform to evaluate B cell–targeted therapeutics en route to the clinic.

Description: Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy. A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression. Here, we sought to optimize noninvasive immuno-PET imaging of human programmed death-ligand 1 (PD-L1) expression, in a preclinical model, using a small high-affinity engineered protein scaffold (HAC-PD1). Six HAC-PD1 radiotracer variants were developed and used in preclinical imaging and biodistribution studies to assess their ability to detect human PD-L1 expression in vivo. Radiotracer design modifications included chelate, glycosylation, and radiometal. HACA-PD1 was adopted as the naming convention for aglycosylated tracer variants. NOD scid -(NSG) mice were inoculated with subcutaneous tumors engineered to either be constitutively positive (CT26 hPD-L1) or be negative (mPD-L1 CT26) for human PD-L1 expression. When the tumors had grown to an average size of 1 cm in diameter, mice were injected with 0.75–2.25 MBq (~10 μg) of an engineered radiotracer variant and imaged. At 1 h after injection, organs were harvested for biodistribution. Of the practical immuno-PET tracer modifications considered, glycosylation was the most prominent design factor affecting tracer uptake, specificity, and clearance. In imaging studies, aglycosylated 64 Cu-NOTA-HACA-PD1 most accurately visualized human PD-L1 expression in vivo. We reasoned that because of the scaffold’s small size (14 kDa), its pharmacokinetics may be suitable for labeling with the short-lived and widely clinically available radiometal 68 Ga. At 1 h after injection, 68 Ga-NOTA-HACA-PD1 and 68 Ga-DOTA-HACA-PD1 exhibited promising target-to-background ratios in ex vivo biodistribution studies (12.3 and 15.2 tumor-to-muscle ratios, respectively). Notably, all HAC-PD1 radiotracer variants enabled much earlier detection of human PD-L1 expression (1 h after injection) than previously reported radiolabeled antibodies (〉24 h after injection). This work provides a template for assessing immuno-PET tracer design parameters and supports the translation of small engineered protein radiotracers for imaging human immune checkpoints.

Description: The recent clinical success of cancer immunotherapy has renewed interest in the development of tools to image the immune system. In general, immunotherapies attempt to enable the body’s own immune cells to seek out and destroy malignant disease. Molecular imaging of the cells and molecules that regulate immunity could provide unique insight into the mechanisms of action, and failure, of immunotherapies. In this article, we will provide a comprehensive overview of the current state-of-the-art immunoimaging toolbox with a focus on imaging strategies and their applications toward immunotherapy.