Targeting endothelial cell anergy to improve CAR T cell therapy for solid tumors.

Chimeric antigen receptor (CAR) T cell therapy presents significant results, especially for the treatment of hematologic malignancies. However, there are limitations and challenges to be overcome to achieve similar success for the treatment of solid tumors. These challenges involve selection of the target, infiltration into the tumor microenvironment and maintenance of functionality. The tumor vasculature is a major barrier for leukocytes to enter the tumor parenchyma. Due to the exposure of the vasculature to angiogenic growth factors during tumor progression, the endothelial cells become anergic to inflammatory cytokines, resulting in reduced leukocyte adhesion molecule expression. As such adhesion molecules are a prerequisite for leukocyte extravasation, endothelial cell anergy allows tumors to escape from endogenous immunity, as well as from cellular immunotherapies such as CAR T cells. Hence, overcoming endothelial cell anergy, e.g. through the administration of angiogenesis inhibitors, is believed to restore anti-tumor immunity. Concomitantly, both endogenous immune cells as well as cellular therapeutics such as CAR T cells can permeate into the tumor parenchyma. Here, we discuss how prior or concomitant treatment with an antiangiogenic drug can improve CAR T cell therapy, to become an attractive strategy for the treatment of solid tumors.

Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy.

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.

Directing CAR T cells towards the tumor vasculature for the treatment of solid tumors.

For successful application of chimeric antigen receptor (CAR) T cell therapy in solid tumors, major hurdles have to be overcome. CAR T cells have to cross the vascular barrier, which is hampered by the anergic state of the tumor vasculature, characterized by suppressed levels of leukocyte adhesion molecules on the endothelium. Additional immunosuppressive mechanisms in the solid tumor microenvironment can affect infiltration, activity and persistence of CAR T cells. Redirecting CAR T cells towards the tumor vasculature poses a possible solution, as molecular targets of tumor endothelial cells can be directly engaged from within the blood. In this review, we discuss recent advances in CAR T cell therapy against solid tumors, with a focus on targeting the tumor vasculature. Furthermore, we discuss opportunities to overcome challenges and barriers through engineering of CAR T cells to enhance trafficking, safety and efficacy.

The tumor vasculature an attractive CAR T cell target in solid tumors.

T cells armed with a chimeric antigen receptor, CAR T cells, have shown extraordinary activity against certain B lymphocyte malignancies, when targeted towards the CD19 B cell surface marker. These results have led to the regulatory approval of two CAR T cell approaches. Translation of this result to the solid tumor setting has been problematic until now. A number of differences between liquid and solid tumors are likely to cause this discrepancy. The main ones of these are undoubtedly the uncomplicated availability of the target cell within the blood compartment and the abundant expression of the target molecule on the cancerous cells in the case of hematological malignancies. Targets expressed by solid tumor cells are hard to engage due to the non-adhesive and abnormal vasculature, while conditions in the tumor microenvironment can be extremely immunosuppressive. Targets in the tumor vasculature are readily reachable by CAR T cells and reside outside the immunosuppressive tumor microenvironment. It is therefore hypothesized that targeting CAR T cells towards the tumor vasculature of solid tumors may share the excellent effects of CAR T cell therapy with that against hematological malignancies. A few reports have shown promising results. Suggestions are provided for further improvement.

Correlation between the Intensity of Helicobacter pylori Colonization and Severity of Gastritis.

BACKGROUND: The most common cause of chronic gastritis is infection with Helicobacter pylori. Identifying the relationship between intensities of colonization and activity of gastritis helps the clinician in more effective treatment and posttreatment follow-ups. METHODS: In this cross-sectional study, endoscopic gastric biopsy samples of 544 patients who complained symptoms of dyspepsia for more than three months referring to the laboratory were studied. To determine the colonization rate of H. pylori and other pathological findings, Giemsa and H&E stains were, respectively, used. RESULTS: Among 544 subjects, 47 (8.64%) patients had no gastritis, 203 (37.32%) had mild gastritis, 278 (10.51%) suffered moderate gastritis, and 16 (2.94%) had severe gastritis. In this study, patients with mild H. pylori colonization rates had the highest level of mild activity (33.52%); in contrast, those with severe H. pylori colonization had the highest level of severe activity (43.75%). 93.96% of people with severe H. pylori colonization suffered from moderate and severe chronic gastritis. There is a significant statistical relationship between the intensity of H. pylori colonization and histopathological findings including intestinal metaplasia, atrophy, and lymphoid follicle formation. CONCLUSIONS: According to the present study, with increasing intensity of H. pylori colonization, chronicity and activity of gastritis and its complications increase.

Intraventricular Hemorrhage in a Term Neonate: Manifestation of Protein S Deficiency- A Case Report.

Protein S (PS) is an antithrombotic plasma protein that plays essential roles in limiting thrombus formation in the anticoagulant system. Protein S deficiency is related with recurrent thrombosis. Here, the authors report a case of a term neonate with severe PS deficiency in year 2015, Imam Hospital, Tehran, Iran, that had seizures and intraventricular hemorrhage (IVH) since the age of 3 days. Nine-month follow-up did not show any developmental problems and MRI showed no hemorrhage.

SLUG and SOX9 Cooperatively Regulate Tumor Initiating Niche Factors in Breast Cancer.

Presence of tumor initiating cells and a proper niche is essential for metastatic colonization. SLUG and SOX9 transcription factors play essential roles in induction and maintenance of tumor initiating capacity in breast cancer cells. On the other hand, Tenascin-C and Periostin are crucial factors in metastatic niche that support tumor initiating capability in breast cancer. In this study, regulatory effect of SLUG and SOX9 transcription factors on the expression of Tenascin-C and Periostin was examined. SLUG and SOX9 were overexpressed and knocked-down in MCF7 and MDA-MB-231 cells, respectively. The cells as little and highly invasive breast cancer-derived cells were infected by inducing and shRNA lentivirus constructs. Then, Tenascin-C and Periostin as well as SLUG and SOX9 expression levels were measured in the cells via Real-Time PCR. Simultaneous overexpression of SLUG and SOX9 significantly induced Tenascin-C and Periostin expression. SLUG and SOX9 knock-down also significantly reduced the expression of Tenascin-C and Periostin. In this analysis Periostin showed the most deviation in both up- and down-regulation levels. This regulatory effect might shed light to a crosstalk between factors involved in the tumor initiating capacity and metastatic niche of the breast cancer.