Carbapenem-resistant (CRE) are major health care-associated pathogens and responsible for hospital outbreaks worldwide. To prevent a further increase in CRE infections and to improve infection prevention strategies, it is important to summarize the current knowledge about CRE infection prevention in hospital settings. This systematic review aimed to identify risk factors for CRE acquisition among hospitalized patients. In addition, we summarized the environmental sources/reservoirs and the most successful infection prevention strategies related to CRE. A total of 3,983 potentially relevant articles were identified and screened. Finally, we included 162 studies in the systematic review, of which 69 studies regarding risk factors for CRE acquisition were included in the random-effects meta-analysis studies. The meta-analyses regarding risk factors for CRE acquisition showed that the use of medical devices generated the highest pooled estimate (odds ratio [OR] = 5.09; 95% confidence interval [CI] = 3.38 to 7.67), followed by carbapenem use (OR = 4.71; 95% CI = 3.54 to 6.26). To control hospital outbreaks, bundled interventions, including the use of barrier/contact precautions for patients colonized or infected with CRE, are needed. In addition, it is necessary to optimize the therapeutic approach, which is an important message to infectious disease specialists, who need to be actively involved in a timely manner in the treatment of patients with known CRE infections or suspected carriers of CRE.

Secreted frizzled-related proteins (SFRP) are glycoproteins containing a so-called frizzled-like cysteine-rich domain. This domain enables them to bind to Wnt ligands or frizzled (FzD) receptors, making potent regulators of Wnt signaling. As Wnt signaling is often altered in cancer, it is not surprising that Wnt regulators such as SFRP proteins are often differentially expressed in the tumor microenvironment, both in a metastatic and non-metastatic setting. Indeed, SFRP2 is shown to be specifically upregulated in the tumor vasculature of several types of cancer. Several studies investigated the functional role of SFRP2 in the tumor vasculature, showing that SFRP2 binds to FzD receptors on the surface of tumor endothelial cells. This activates downstream Wnt signaling and which is, thereby, stimulating angiogenesis. Interestingly, not the well-known canonical Wnt signaling pathway, but the noncanonical Wnt/Ca2+ pathway seems to be a key player in this event. In tumor models, the pro-angiogenic effect of SFRP2 could be counteracted by antibodies targeting SFRP2, without the occurrence of toxicity. Since tumor angiogenesis is an important process in tumorigenesis and metastasis formation, specific tumor endothelial markers such as SFRP2 show great promise as targets for anti-cancer therapies. This review discusses the role of SFRP2 in noncanonical Wnt signaling and tumor angiogenesis, and highlights its potential as anti-angiogenic therapeutic target in cancer.

Anti-angiogenic cancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional secretion mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions. Antibody targeting of extracellular vimentin shows inhibition of angiogenesis in vitro and in vivo. Effective and safe inhibition of angiogenesis and tumor growth in several preclinical and clinical studies is demonstrated using a vaccination strategy against extracellular vimentin. Targeting vimentin induces a pro-inflammatory condition in the tumor, exemplified by induction of the endothelial adhesion molecule ICAM1, suppression of PD-L1, and altered immune cell profiles. Our findings show that extracellular vimentin contributes to immune suppression and functions as a vascular immune checkpoint molecule. Targeting of extracellular vimentin presents therefore an anti-angiogenic immunotherapy strategy against cancer.

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BackgroundOX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in the treatment of patients with cancer has fallen short of the high expectation in earlier-stage trials.MethodsUsing lymphocytes from resected tumor, tumor-free (TF) tissue and peripheral blood mononuclear cells (PBMC) of 96 patients with hepatocellular and colorectal cancers, we determined OX40 expression and the in vitro T-cell agonistic activity of OX40-targeting compounds. RNA-Seq was used to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs).ResultsHere, we show that OX40 was overexpressed on tumor-infiltrating CD4+ T cells compared with blood and TF tissue-derived T cells. In contrast to a clinical candidate αOX40 antibody, treatment with an Fc-engineered αOX40 antibody (αOX40_v12) with selectively enhanced FcγRIIB affinity, stimulated in vitro CD4+ and CD8+ TIL expansion, as well as cytokine and chemokine secretions. The activity of αOX40_v12 was dependent on FcγRIIB engagement and intrinsic CD3/CD28 signals. The transcriptional landscape of CD4+ and CD8+ TILs shifted toward a prosurvival, inflammatory and chemotactic profile on treatment with αOX40_v12.ConclusionsOX40 is overexpressed on CD4+ TILs and thus represents a promising target for immunotherapy. Targeting OX40 with currently used agonistic antibodies may be inefficient due to lack of OX40 multimerization. Thus, Fc engineering is a powerful tool in enhancing the agonistic activity of αOX40 antibody and may shape the future design of antibody-mediated αOX40 immunotherapy.

Extracellular vimentin is a specific marker of the tumor vasculature, where it is secreted by tumor endothelial cells. Vaccination with a conjugate vaccine targeting extracellular vimentin was previously shown to induce a potent humoral immune response and tumor growth inhibition in mice. These data were obtained by vaccination using the toxic Freund’s adjuvant (FA) and are therefore not directly translatable into the clinic. In the present study, we aimed to investigate the potential of the biodegradable Montanide ISA 720 adjuvant. We tested Montanide either alone (MN) or supplemented with CpG 1826 (MN-C). Both adjuvant compositions, as well as FA, resulted in a significant tumor growth inhibition and decreased vessel density in the B16F10 melanoma tumor model. Vaccination of mice with either FA or MN-C resulted in an equally potent humoral immune response towards vimentin, while the antibody titers obtained with MN alone were significantly lower compared to FA. Vaccination coincided with the infiltration of immune cells. The highest number of intratumoral immune cells was seen in tumors from the MN-C group. Therefore, we conclude that Montanide ISA 720 supplemented with CpG allows efficient vaccination against extracellular vimentin, which is a prerequisite for the transfer of the vaccine into the clinic.

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BackgroundAngiogenesis, the development of neovasculature, is required to sustain tumor growth and metastasis of solid tumors. The tumor neovasculature expresses specific markers, which are selectively overexpressed in tumor endothelial cells compared to normal healthy adult endothelium and are therefore ideal targets for vaccination.MethodsOne of these tumor vascular markers is the extracellular cytoskeletal protein vimentin. This marker is externalized from tumor endothelial cells, while expression in all other cells in the body is exclusively intracellular. Extracellular vimentin (eVim) is pro-angiogenic and functionally mimics vascular endothelial growth factor (VEGF) action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions, thereby hampering leukocyte infiltration into the tumor. eVim is overexpressed in the vasculature of different solid tumors, but not present in normal healthy tissue.ResultsUsing iBoost, our proprietary conjugate vaccine technology for induction of efficient antibody responses against self-antigens, we were able to generate strong eVim specific humoral immune responses, resulting in inhibition of tumor growth in preclinical models without affecting the normal healthy vasculature. Furthermore, in an ongoing clinical study in client owned dogs with spontaneous bladder cancer our eVim vaccine shows effective and safe inhibition of angiogenesis and tumor growth.ConclusionsTargeting of extracellular vimentin by vaccination therefore presents a promising antiangiogenic immunotherapy strategy that is currently translated into clinical testing.