CD1d-Invariant Natural Killer T Cell-Based Cancer Immunotherapy: α-Galactosylceramide and Beyond

CD1d-restricted invariant natural killer T (iNKT) cells are considered an attractive target for cancer immunotherapy. Upon their activation by glycolipid antigen and/or cytokines, iNKT cells can induce direct lysis of tumor cells but can also induce an antitumor immune response via their rapid production of proinflammatory cytokines that trigger the cytotoxic machinery of other components of the innate and adaptive immune system. Here, we provide an overview of various therapeutic approaches that have been evaluated or that are currently being developed and/or explored. These include administration of α-GalCer or alternative (glyco) lipid antigens, glycolipid-loaded antigen-presenting cells and liposomes, strategies that enhance CD1d expression levels or are based on ligation of CD1d, adoptive transfer of iNKT cells or chimeric antigen receptor iNKT cells, and tumor targeting of iNKT cells

Corrigendum: CD1d-Invariant Natural Killer T Cell-Based Cancer Immunotherapy: α-Galactosylceramide and Beyond

by King, L. A., Lameris, R., de Gruijl, T. D., and van der Vliet, H. J. (2018). Front. Immunol. 9:1519. doi: 10.3389/fimmu.2018.01519 In the original article, we neglected to disclose that authors Lisa A. King and Roeland Lameris are currently funded by Lava Therapeutics and that Hans J. van der Vliet also acts as chief scientific officer of Lava Therapeutics. Hans J. van der Vliet's affiliation has been updated to reflect this. The corrected Conflict of Interest statement appears below

Systematically Developing a Web-Based Tailored Intervention Promoting HPV-Vaccination Acceptability Among Mothers of Invited Girls Using Intervention Mapping.

Background: Currently, the eHealth field calls for detailed descriptions of theory-based interventions in order to support improved design of such interventions. This article aims to provide a systematic description of the design rationale behind an interactive web-based tailored intervention promoting HPV-vaccination acceptability. Methods: The 6-step Intervention Mapping (IM) protocol was used to describe the design rationale. After the needs assessment in Step 1, intervention objectives were formulated in Step 2. In Step 3, we translated theoretical methods into practical applications, which were integrated into a coherent intervention in Step 4. In Step 5, we anticipated future implementation and adoption, and finally, an evaluation plan was generated in Step 6. Results: Walking through the various steps of IM resulted in a detailed description of the intervention. The needs assessment indicated HPV-vaccination uptake remaining lower than expected. Mothers play the most important role in decision-making about their daughter's immunization. However, they generally feel ambivalent after they made their decisions, and their decisions are based on rather unstable grounds. Therefore, intervention objectives were to improve HPV-vaccination uptake and informed decision-making, and to decrease decisional conflict among mothers of invited girls. Computer-tailoring was chosen as the main method; virtual assistants were chosen as a practical application to deliver interactive tailored feedback. To maximize compatibility with the needs of the target group, a user-centered design strategy by means of focus groups and online experiments was applied. In these, prototypes were tested and sequentially refined. Finally, efficacy, effectiveness, and acceptability of the intervention were tested in a randomized controlled trial. Results showed a significant positive effect of the intervention on informed decision-making, decisional conflict, and nearly all determinants of HPV-vaccination uptake (P < 0.001). Mothers evaluated the intervention as highly positive. Discussion: Using IM led to an innovative effective intervention for promoting HPV-vaccination acceptability. The intervention maps will aid in interpreting the results of our evaluation studies. Moreover, it will ease the comparison of design rationales across interventions, and may provide leads for the development of other eHealth interventions. This paper adds to the plea for systematic reporting of design rationales constituting the process of developing interventions

Helicobacter pylori Modulates the T Helper Cell 1/T Helper Cell 2 Balance through Phase-variable Interaction between Lipopolysaccharide and DC-SIGN

The human gastric pathogen Helicobacter pylori spontaneously switches lipopolysaccharide (LPS) Lewis (Le) antigens on and off (phase-variable expression), but the biological significance of this is unclear. Here, we report that Le+ H. pylori variants are able to bind to the C-type lectin DC-SIGN and present on gastric dendritic cells (DCs), and demonstrate that this interaction blocks T helper cell (Th)1 development. In contrast, Le− variants escape binding to DCs and induce a strong Th1 cell response. In addition, in gastric biopsies challenged ex vivo with Le+ variants that bind DC-SIGN, interleukin 6 production is decreased, indicative of increased immune suppression. Our data indicate a role for LPS phase variation and Le antigen expression by H. pylori in suppressing immune responses through DC-SIGN

Positive & Negative Roles of Innate Effector Cells in Controlling Cancer Progression

Innate immune cells are active at the front line of host defense against pathogens and now appear to play a range of roles under non-infectious conditions as well, most notably in cancer. Establishing the balance of innate immune responses is critical for the “flavor” of these responses and subsequent adaptive immunity and can be either “good or bad” in controlling cancer progression. The importance of innate NK cells in tumor immune responses has already been extensively studied over the last few decades, but more recently several relatively mono- or oligo-clonal [i.e., (semi-) invariant] innate T cell subsets received substantial interest in tumor immunology including invariant natural killer T (iNKT), γδ-T and mucosal associated invariant T (MAIT) cells. These subsets produce high levels of various pro- and/or anti-inflammatory cytokines/chemokines reflecting their capacity to suppress or stimulate immune responses. Survival of patients with cancer has been linked to the frequencies and activation status of NK, iNKT, and γδ-T cells. It has become clear that NK, iNKT, γδ-T as well as MAIT cells all have physiological roles in anti-tumor responses, which emphasize their possible relevance for tumor immunotherapy. A variety of clinical trials has focused on manipulating NK, iNKT, and γδ-T cell functions as a cancer immunotherapeutic approach demonstrating their safety and potential for achieving beneficial therapeutic effects, while the exploration of MAIT cell related therapies is still in its infancy. Current issues limiting the full therapeutic potential of these innate cell subsets appear to be related to defects and suppressive properties of these subsets that, with the right stimulus, might be reversed. In general, how innate lymphocytes are activated appears to control their subsequent abilities and consequent impact on adaptive immunity. Controlling these potent regulators and mediators of the immune system should enable their protective roles to dominate and their deleterious potential (in the specific context of cancer) to be mitigated

A Large Outbreak of Legionnaires’ Disease at a Flower Show, the Netherlands, 1999

In 1999, an outbreak of Legionnaires’ disease affected many visitors to a flower show in the Netherlands. To identify the source of the outbreak, we performed an environmental investigation, as well as a case-control study among visitors and a serologic cohort study among exhibitors to measure exposure to possible sources. Of 77,061 visitors, 188 became ill (133 confirmed and 55 probable cases), for an attack rate of 0.23% for visitors and 0.61% for exhibitors. Two whirlpool spas in halls 3 and 4 of the exhibition and a sprinkler in hall 8 were culture positive for Legionella pneumophila. One of three genotypes found in both whirlpool spas was identical to the isolates from 28 of 29 culture-positive patients. Persons who paused at the whirlpool spa in hall 3 were at increased risk for becoming ill. This study illustrates that whirlpool spas may be an important health hazard if disinfection fails

Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

<p>Abstract</p> <p>Background</p> <p>For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide.</p> <p>Methods/design</p> <p>This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels.</p> <p>Discussion</p> <p>This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell carcinoma and increase the antitumor efficacy of everolimus.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT01462214">NCT01462214</a>, EudraCT number 2010-024515-13, Netherlands Trial Register number <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2040">NTR3085</a>.</p

Ruthenium polypyridyl complexes and their modes of interaction with DNA : is there a correlation between these interactions and the antitumor activity of the compounds?

Various interaction modes between a group of six ruthenium polypyridyl complexes and DNA have been studied using a number of spectroscopic techniques. Five mononuclear species were selected with formula [Ru(tpy) L1L2](2-n)?, and one closely related dinuclear cation of formula [{Ru(apy)(tpy)}2{l-H2N(CH2)6NH2}]4?. The ligand tpy is 2,20:60,200-terpyridine and the ligand L1 is a bidentate ligand, namely, apy (2,20-azobispyridine), 2-phenylazopyridine, or 2-phenylpyridinylmethylene amine. The ligand L2 is a labile monodentate ligand, being Cl-, H2O, or CH3CN. All six species containing a labile L2 were found to be able to coordinate to the DNA model base 9-ethylguanine by 1H NMR and mass spectrometry. The dinuclear cationic species, which has no positions available for coordination to a DNA base, was studied for comparison purposes. The interactions between a selection of four representative complexes and calf-thymus DNA were studied by circular and linear dichroism. To explore a possible relation between DNA-binding ability and toxicity, all compounds were screened for anticancer activity in a variety of cancer cell lines, showing in some cases an activity which is comparable to that of cisplatin. Comparison of the details of the compound structures, their DNA binding, and their toxicity allows the exploration of structure–activity relationships that might be used to guide optimization of the activity of agents of this class of compounds

Hotspots of uncertainty in land-use and land-cover change projections: a global-scale model comparison

Model-based global projections of future land use and land cover (LULC) change are frequently used in environmental assessments to study the impact of LULC change on environmental services and to provide decision support for policy. These projections are characterized by a high uncertainty in terms of quantity and allocation of projected changes, which can severely impact the results of environmental assessments. In this study, we identify hotspots of uncertainty, based on 43 simulations from 11 global-scale LULC change models representing a wide range of assumptions of future biophysical and socio-economic conditions. We attribute components of uncertainty to input data, model structure, scenario storyline and a residual term, based on a regression analysis and analysis of variance. From this diverse set of models and scenarios we find that the uncertainty varies, depending on the region and the LULC type under consideration. Hotspots of uncertainty appear mainly at the edges of globally important biomes (e.g. boreal and tropical forests). Our results indicate that an important source of uncertainty in forest and pasture areas originates from different input data applied in the models. Cropland, in contrast, is more consistent among the starting conditions, while variation in the projections gradually increases over time due to diverse scenario assumptions and different modeling approaches. Comparisons at the grid cell level indicate that disagreement is mainly related to LULC type definitions and the individual model allocation schemes. We conclude that improving the quality and consistency of observational data utilized in the modeling process as well as improving the allocation mechanisms of LULC change models remain important challenges. Current LULC representation in environmental assessments might miss the uncertainty arising from the diversity of LULC change modeling approaches and many studies ignore the uncertainty in LULC projections in assessments of LULC change impacts on climate, water resources or biodiversity