'Relation, association, attribution ...' – the multiple faces of death in critical care medicine

Mortality is one of the most important quality markers in critical care, and there have been many epidemiological studies trying to identify risk factors to better understand the mechanisms leading to death in this complex disease. One of the major problems is that there are multiple factors contributing to fatal outcome of septic patients, and it is difficult to distinguish between those that are independent from the acute disease (comorbidities and 'risk factors') and those that are directly involved in the pathomechanisms of sepsis, thus leading to the 'sepsis-attributable' mortality. In this short commentary, some examples of different approaches of how to analyze data on mortality are presented

Managing septic shock

Although several successful clinical trials in the last 2-3 years have been greeted with enthusiasm by intensivists, severe sepsis and septic shock still have increasing incidence and more or less unchanged mortality. Within the last few years, the progress in sepsis research covering definitions, epidemiology, pathophysiology, diagnosis, and standard and adjunctive therapy as well as general measures such as treatment bundles is encouraging. In this report, a small selection of recent publications, focusing on the current discussion of activated protein C as well as the relevance of the Surviving Sepsis Campaign bundle therapy, is presented and the possible impact on clinical routine is discussed

Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype

Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8$^{+}$ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8$^{+}$ T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC

Vaccination with designed neopeptides induces intratumoral, cross-reactive CD4+ T cell responses in glioblastoma

Purpose: The low mutational load of some cancers is considered one reason for the difficulties to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutation to enhance their immunogenicity. Experimental Design: Exome- and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides. Subsequently, in silico HLA-anchor placements were used to deduce putative T cell receptor contacts of peptides. Single amino acids of TCR contacting residues were then mutated by amino acid replacements. Overall, 175 peptides were synthesized and sets of 25 each containing both peptides designed to bind to HLA class I and II molecules applied in the vaccination. Upon development of a tumor recurrence, the tumor-infiltrating lymphocytes (TILs) were characterized in detail both at the bulk and clonal level. Results: The immune response of peripheral blood T cells to vaccine peptides, including natural peptides and designed neopeptides, gradually increased with repetitive vaccination, but remained low. In contrast, at the time of tumor recurrence, CD8+ TILs and CD4+ TILs responded to 45% and 100% respectively of the vaccine peptides. Further, TIL-derived CD4+ T cell clones showed strong responses and tumor cell lysis not only against the designed neopeptide but also against the unmutated natural peptides of the tumor. Conclusions: Turning tumor self-peptides into foreign antigens by introduction of designed mutations is a promising strategy to induce strong intratumoral CD4+ T cell responses in a cold tumor like glioblastoma