Genetically engineered T cells expressing a chimeric antigen receptor (CAR) are rapidly emerging a promising new treatment for haematological and non-haematological malignancies. CAR-T therapy can induce rapid and durable clinical responses but is associated with unique acute toxicities. Moreover, CAR-T cells are vulnerable to immunosuppressive mechanisms. Here, we report that CAR-T cells release extracellular vesicles, mostly in the form of exosomes that carry CAR on their surface. The CAR-containing exosomes express a high level of cytotoxic molecules and inhibit tumour growth. Compared with CAR-T cells, CAR exosomes do not express Programmed cell Death protein 1 (PD1), and their antitumour effect cannot be weakened by recombinant PD-L1 treatment. In a preclinical in vivo model of cytokine release syndrome, the administration of CAR exosomes is relatively safe compared with CAR-T therapy. This study supports the use of exosomes as biomimetic nanovesicles that may be useful in future therapeutic approaches against tumours.

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Recent studies have shown that some members of the tripartite motif-containing protein (TRIM) family serve as important regulators of tumorigenesis. However, the biological role of TRIM14 in osteosarcoma remains to be established. In this study, we showed that TRIM14 is upregulated in human osteosarcoma specimens and cell lines, and correlated with osteosarcoma progression and shorter patient survival times. Functional studies demonstrated that overexpression of TRIM14 enhances osteosarcoma cell proliferation, clone formation, cell cycle procession, migration and invasion in vitro and promotes tumor growth in vivo, and conversely, its silencing has the opposite effects. Furthermore, TRIM14 overexpression induced activation of the AKT pathway. Inhibition of AKT expression reversed the TRIM14-mediated promotory effects on cell growth and mobility, in addition to TRIM14-induced epithelial-to-mesenchymal transition (EMT) and cyclin D1 upregulation. Our findings collectively suggest that TRIM14 functions as an oncogene by upregulating the AKT signaling pathway in osteosarcoma cells, supporting its potential utility as a therapeutic target for this disease.

BackgroundReports indicate social distancing guidelines and other effects of the COVID-19 pandemic impacted trauma patient volumes and injury patterns. This report is the first analysis of a large trauma network describing the extent of these impacts. The objective of this study was to describe the effects of the COVID-19 pandemic on patient volumes, demographics, injury characteristics, and outcomes.MethodsFor this descriptive, multicenter study from a large, multistate hospital network, data were collected from the system-wide centralized trauma registry and retrospectively reviewed to retrieve patient information including volume, demographics, and outcomes. For comparison, patient data from January through May of 2020 and January through May of 2019 were extracted.ResultsA total of 12 395 trauma patients (56% men, 79% white, mean age 59 years) from 85 trauma centers were included. The first 5 months of 2020 revealed a substantial decrease in volume, which began in February and continued into June. Further analysis revealed an absolute decrease of 32.5% in patient volume in April 2020 compared with April 2019 (4997 from 7398; p<0.0001). Motor vehicle collisions decreased 49.7% (628 from 1249). There was a statistically significant increase in injury severity score (9.0 vs. 8.3; p<0.001). As a proportion of the total trauma population, blunt injuries decreased 3.1% (87.3 from 90.5) and penetrating injuries increased 2.7% (10.0 from 7.3; p<0.001). A significant increase was found in the proportion of patients who did not survive to discharge (3.6% vs. 2.8%; p=0.010; absolute decrease: 181 from 207).DiscussionEarly phases of the COVID-19 pandemic were associated with a 32.5% decrease in trauma patient volumes and altered injury patterns at 85 trauma centers in a multistate system. This preliminary observational study describes the initial impact of the COVID-19 pandemic and warrants further investigation.Level of evidenceLevel II (therapeutic/care management).

Epidermal growth factor receptor (EGFR) blockade and radiation are efficacious in the treatment of cancer, but resistance is commonly reported. Studies have suggested that dysregulation of Notch signaling and enrichment of the cancer stem cell population underlie these treatment challenges. Our data show that dual targeting of EGFR and Notch2/3 receptors with antibody CT16 not only inhibited signaling mediated by these receptors but also showed a strong anti-stem cell effect both in vitro and in vivo. Treatment with CT16 prevented acquired resistance to EGFR inhibitors and radiation in non-small cell lung cancer (NSCLC) cell line models and patient-derived xenograft tumors. CT16 also had a superior radiosensitizing impact compared with EGFR inhibitors. CT16 in combination with radiation had a larger antitumor effect than the combination of radiation with EGFR inhibitors or tarextumab. Mechanistically, CT16 treatment inhibits the stem cell-like subpopulation, which has a high mesenchymal gene expression and DNA repair activity, and reduces tumor-initiating cell frequency. This finding highlights the capacity of a combined blockade of EGFR and Notch signaling to augment the response to radiation and suggests that CT16 may achieve clinical efficacy when combined with radiation in NSCLC treatment.