Immunotherapy that is based on adoptive transfer of T lymphocytes, which are genetically modified to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens, has been demonstrated to be an efficient cancer therapy. Vascular endothelial growth factor receptor-1 (VEGFR-1), a vital molecule involved in tumor growth and angiogenesis, has not been targeted by CAR-modified T lymphocytes. In this study, we generated CAR-modified T lymphocytes with human VEGFR-1 specificity (V-1 CAR) by electroporation. V-1 CAR-modified T lymphocytes were demonstrated to elicit lytic cytotoxicity to target cells in a VEGFR-1-dependent manner. The adoptive transfer of V-1 CAR T lymphocytes delayed tumor growth and formation and inhibited pulmonary metastasis in xenograft models and such efficacies were enhanced by cotransfer of T lymphocytes that expressed interleukin-15 (IL-15). Moreover, V-1 CAR-modified T lymphocytes lysed primary endothelial cells and impaired tube formation, in vitro. These data demonstrated the antitumor and anti-angiogenesis ability of V-1 CAR-modified T lymphocytes. Our study provides the rationale for the clinical translation of CAR-modified T lymphocytes with VEGFR-1 specificity.
MicroRNAs are endogenous, non-coding RNAs of approximately 20-22 nucleotides that regulate genes expression by binding to the 3' untranslated region (UTR) of targets mRNAs and play critical roles in cancer pathways. Malignant glioma is the most common and highly lethal central nervous system tumor for which little effective treatment is available over several decades. The purpose of this study was to explore the therapeutic potential of plasmid-based microRNA-7 (miR-7) for gliomas in vivo. Enhancing miR-7 levels in vitro could significantly induce cell apoptosis, and inhibit cell proliferation, cell migration and invasion. Western blotting analysis was performed, which indicated that miR-7 directly inhibited epidermal growth factor receptor (EGFR) and further antagonized the downstream protein kinases including ERK, Akt and Stat3. Furthermore, systemic administration of miR-7 encapsulated in cationic liposome resulted in glioma xenografts growth arrest and the metastatic nodules decrease effectively in a sequence-specific manner. In this study, miR-7 was applied in glioma treatment for the first time in vivo. Our findings suggested that the plasmid-mediated gene therapy with miR-7 appeared to be a promising candidate for the development of new antitumor and anti-metastasis treatment for human glioma.
Chimeric antigen receptor-modified T cells (CAR-T) are endowed with cytotoxic specificity to tumor cells. Although CAR-T-based cancer immunotherapy presents curable therapeutic potential for hematological malignancies, achieving substantial efficacy for solid tumors remain challenging. Researchers have exploited many strategies to enhance the anti-tumor efficacy of CAR-T cells for solid tumors, among which cytokine-armed CAR-T cells improve the proliferation, survival, homing and other properties of CAR-T cells. Interleukins (ILs), pivotal cytokines that affect the function of immune cells, were co-expressed in CAR-T cells or combinatorially administered to enhance the therapeutic potential in clinical trials. In this review, we summarize the strategies exploited by ILs to improve the anti-cancer ability of CAR-T cells and the different impacts of different ILs on CAR-T cells.
Aim: To evaluate risk factors for venous thromboembolism (VTE) and deep vein thrombosis after living donor nephrectomy in a centre using extensive preoperative screening and perioperative venous duplex scan. Material and Methods: In 130 consecutive living kidney donors (laparoscopic 105, open 25) thrombophilia screening and pre-and postoperative ultrasonographies were performed. Donors were followed prospectively for at least 3 months. All donors received prophylaxis with the low molecular weight heparin enoxaparin and compression stockings. Donors with increased risk received the double dose of enoxaparin and the prophylaxis was continued for 6 weeks. Donors with venous thrombosis at discharge duplex also received prolonged prophylaxis. Results: The frequency of thrombophilia was similar to what can be expected in the Swedish population (four with factor V Leiden, one each with protein S defi ciency, prothrombin gene mutation and anticardiolipin antibodies). Preoperative duplex was normal. Three donors had small postoperative deep vein thrombosis. Twelve donors (9,2%) received an intensifi ed and prolonged prophylaxis. No further thromboembolic complications developed in three postoperative months. Conclusion: With the present protocol for preoperative evaluation, perioperative duplex screening and prophylaxis, the risk of postoperative venous thromboembolism is low after living donor nephrectomy. Given that 9,2% had risk factors or developed deep vein thrombosis and the extraordinary situation where an operation is performed on a healthy person who has no therapeutic benefi t and the low incidence of VTE in the present study, we recommend the presented approach to be implemented more broadly and that further studies should be performed in larger cohorts.
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