In vitro-transcribed messenger RNA-based therapeutics represent a relatively novel and highly efficient class of drugs. Several recently published studies emphasize the potential efficacy of mRNA vaccines in treating different types of malignant and infectious diseases where conventional vaccine strategies and platforms fail to elicit protective immune responses. mRNA vaccines have lately raised high interest as potent vaccines against SARS-CoV2. Direct application of mRNA or its electroporation into dendritic cells was shown to induce polyclonal CD4+ and CD8+ mediated antigen-specific T cell responses as well as the production of protective antibodies with the ability to eliminate transformed or infected cells. More importantly, the vaccine composition may include two or more mRNAs coding for different proteins or long peptides. This enables the induction of polyclonal immune responses against a broad variety of epitopes within the encoded antigens that are presented on various MHC complexes, thus avoiding the restriction to a certain HLA molecule or possible immune escape due to antigen-loss. The development and design of mRNA therapies was recently boosted by several critical innovations including the development of technologies for the production and delivery of high quality and stable mRNA. Several technical obstacles such as stability, delivery and immunogenicity were addressed in the past and gradually solved in the recent years.This review will summarize the most recent technological developments and application of mRNA vaccines in clinical trials and discusses the results, challenges and future directions with a special focus on the induced innate and adaptive immune responses.

Many patients with squamous cell carcinoma of the head and neck (SCCHN) are ≥65 years old; comorbidities and other age-related factors may affect their ability to tolerate traditional chemotherapy. Nivolumab is the only immunotherapy to significantly improve overall survival (OS) versus investigator's choice (IC) of single-agent chemotherapy at primary analysis in a phase 3 trial (CheckMate 141) in patients with recurrent/metastatic SCCHN post-platinum therapy. In this post hoc analysis, we report efficacy and safety by age. Eligible patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks (n = 240) or IC (methotrexate, docetaxel, or cetuximab n = 121). The primary endpoint of the trial was OS. For this analysis, outcomes were analyzed by age < 65 and ≥65 years. The data cut-off date was September 2017 (minimum follow-up 24.2 months). At baseline, 68 patients (28.3%) receiving nivolumab and 45 patients (37.2%) receiving IC were ≥65 years. Baseline characteristics were generally similar across age groups. OS and tumor response benefits with nivolumab versus IC were maintained regardless of age. The 30-month OS rates of 11.2% (<65 years) and 13.0% (≥65 years) with nivolumab were more than tripled versus corresponding IC rates of 1.4% and 3.3%, respectively. The nivolumab arm had a lower rate of treatment-related adverse events versus IC regardless of age, consistent with the overall patient population. In CheckMate 141, nivolumab resulted in a higher survival versus IC in patients <65 and ≥65 years, with a manageable safety profile in both age groups. ClinicalTrials.gov: NCT02105636.

Background: The majority of patients with recurrent or metastasized head and neck squamous cell carcinoma (HNSCC) do not benefit from immune checkpoint blockade (ICB) while several patients experience severe and persistent immune-mediated side effects. Therefore, predictive biomarkers are urgently needed to allow for a personalized treatment. In this study, we investigated DNA methylation of the immune checkpoint gene CTLA4 with regard to its predictive value. Methods: We analyzed CTLA4 promoter methylation in tumors of HNSCC patients (N = 29) treated with ICB at the University Medical Center Bonn with regard to response to ICB and progression-free survival. We further analyzed a second cohort (N = 138) of patients that did not receive ICB with regard to CTLA4 promoter methylation, CTLA-4 protein expression, and immune cell infiltrates. Finally, we tested inducibility of CTLA-4 protein expression in HNSCC cells using the DNA methyltransferase inhibitor decitabine. Results: Lower CTLA4 promoter methylation correlated with response to ICB and prolonged progression-free survival. We could show that not only tumor infiltrating immune cells, but also HNSCC cells harbor cytoplasmic and nuclear CTLA-4 expression. CTLA4 promoter methylation inversely correlated with infiltrates of CD3⁺, CD4⁺, CD8⁺, and CD45⁺ immune cells. CTLA4 methylation did not correlate with protein expression in tumors, however, decitabine treatment led to decreased CTLA4 methylation and an induction of CTLA4 mRNA and CTLA-4 protein expression in HNSCC cell lines. Conclusions: Our results indicate that CTLA4 DNA hypomethylation is a predictive biomarker for response to ICB in HNSCC. Our study warrants further analyses of the predictive value of CTLA4 DNA methylation in clinical trials of anti-PD-1 and/or anti-CTLA-4 immunotherapy in HNSCC.

Giant cell arteritis is the most common form of large vessel vasculitis and preferentially involves large and medium-sized arteries in patients over the age of 50. Aggressive wall inflammation, neoangiogenesis and consecutive remodeling processes are the hallmark of the disease. Though etiology is unknown, cellular and humoral immunopathological processes are well understood. Matrix metalloproteinase-9 mediated tissue infiltration occurs through lysis of basal membranes in adventitial vessels. CD4+ cells attain residency in immunoprotected niches, differentiate into vasculitogenic effector cells and enforce further leukotaxis. Signaling pathways involve the NOTCH1-Jagged1 pathway opening vessel infiltration, CD28 mediated T-cell overstimulation, lost PD-1/PD-L1 co-inhibition and JAK/STAT signaling in interferon dependent responses. From a humoral perspective, IL-6 represents a classical cytokine and potential Th-cell differentiator whereas interferon-γ (IFN- γ) has been shown to induce chemokine ligands. Current therapies involve glucocorticoids, tocilizumab and methotrexate application. However, new agents, most notably JAK/STAT inhibitors, PD-1 agonists and MMP-9 blocking substances, are being evaluated in ongoing clinical trials.

Background: The worldwide COVID-19 pandemic has initiated a change in medical education and the development of new teaching concepts has become inevitable to maintain adequate training. Objective: This pilot study aims to compare teledidactic teaching with traditional face-to-face teaching for abdominal, thoracic, and thyroid ultrasound. Design: Concurrently, a teledidactic and a face-to-face ultrasound course were held. The students completed seven 90-min modules using mobile ultrasound probes (Butterfly IQ). Each module consisted of a lecture, a demonstration of probe guidance, and independent training. Participants: A total of thirty medical students took part in the study and were randomly assigned to a teledidactic and a face-to-face group. Main Measures: An objective structured assessment of ultrasound skills (OSAUS) was performed as a pre-test and as the final exam and ultrasound images obtained during the exam were evaluated using the brightness mode quality ultrasound imaging examination (B-QUIET) scale. Key Results: No significant difference between the two cohorts on the OSAUS final exam was shown (p > 0.05 in all modules). There was a significant difference in the assessment of the images in the focused assessment with sonography for trauma (FAST) (p 0.015) and aorta (p 0.017) modules. Students in the teledidactic group performed better in both modules, scoring 33.59 (± 2.61) out of 44 in the module FAST (face-to-face group 30.95 (± 1.76)) and aortic images averaged 35.41 (± 2.61) points (face-to-face group 32.35 (± 3.08)). Conclusions: A teledidactic course for abdominal and thoracic ultrasound examinations is equally effective to traditional face-to-face teaching in this pilot study. Digital implementation with a portable ultrasound machine could be a great opportunity to promote ultrasound education worldwide and over great distances.

Modern irradiation techniques for optimized conformal TBI can be realized by Helical Tomotherapy (HT) or Volumetric Modulated Arc Therapy (VMAT), depending on the availability of suitable specialized equipment. In this dosimetric planning study, we compared both modalities and addressed the question of whether VMAT with small field sizes is also suitable as a backup in case of HT equipment malfunctions. For this purpose, we retrospectively used planning computed tomography (CT) data from 10 patients treated with HT with a total dose of 8 Gy (n = 5) or 12 Gy (n = 5) for treatment planning for VMAT with a small field size (36 × 22 cm). The target volume coverage, dose homogeneity at target volume, and dose reduction in organs at risk (OAR) (lungs, kidneys, lenses) were analyzed and compared. One patient was irradiated with both modalities due to a device failure of the HT equipment during the study, which facilitated a comparison in a real clinical setting. The findings indicate that in addition to a higher mean dose to the lenses in the 12 Gy group for VMAT and a better dose homogeneity in the target volume for HT, comparably good and adequate target dose coverage and dose reduction in the other OAR could be achieved for both modalities, with significantly longer treatment times for VMAT. In conclusion, after appropriate optimization of the treatment times, VMAT using linear accelerator radiosurgery technology can be used both as a backup in addition to HT and in clinical routines to perform optimized conformal TBI.