Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and immune cells leads to tumor ...resistance to oncolytic immunotherapy. In this study, we generate an engineered oncolytic virus that coexpresses a PD-L1 inhibitor and GM-CSF. We find that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Importantly, the intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. In summary, this engineered oncolytic virus is able to activate tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.
Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new ...anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138 ). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2 × 10
-4 × 10
CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy.
The selective accumulation and real‐time monitoring of drug release at tumor site are the key bottlenecks to the clinical translation of polyprodrug. Herein, an intracellular self‐immolative ...polyprodrug (PMTO) is exploited, which not only shows the enhanced cellular internalization and selective accumulation in tumor site under the mild hyperthermia triggered by laser irradiation, but also possesses the self‐monitoring drug release ability in vivo. The polyprodrug amphiphiles are synthesized by sequential esterification reaction, and hydrophilic poly(ethylene glycol) serves as blocking agent. On account of the mild hyperthermia produced by PMTO under the laser irradiation at tumor site, the cell membranous permeability increases, resulting in the enhanced cellular internalization and drug accumulation in tumor. After internalized by cells, the self‐immolative PMTO nanoparticles can release free mitoxantrone (MTO) in intracellular reductive environment, and ratiometric photoacoustic imaging based on distinct signals between MTO and PMTO is presented to trace the drug release in vivo. Finally, this self‐monitoring polyprodrug presents significant tumor suppression efficacy, which exhibits great potential for guiding the clinical medication in cancer treatment.
An intracellular self‐immolative polyprodrug (PMTO) is developed, wherein the drug accumulation in tumor is significantly enhanced under laser‐triggered mild hyperthermia, and the drug release behavior is real‐time monitored by ratiometric photoacoustic signals. PMTO holds great potential for enhanced targeted chemotherapy efficacy as well as the visualization of drug release in vivo, guiding the clinical medication in cancer treatment.
As a characteristic trait of most tumor types, metastasis is the major cause of the death of patients. In this study, a photothermal agent based on gold nanorod is coated with metal (Gd3+)‐organic ...(polyphenol) network to realize combination therapy for metastatic tumors. This nanotheranostic system significantly enhances antitumor therapeutic effects in vitro and in vivo with the combination of photothermal therapy (PTT) and chemotherapy, also can remarkably prevent the invasion and metastasis due to the presence of polyphenol. After the treatment, an 81% decrease in primary tumor volumes and a 58% decrease in lung metastasis are observed. In addition, the good performance in magnetic resonance imaging, computerized tomography, and photothermal imaging of the nanotheranostic system can realize image‐guided therapy. The multifunctional nanotheranostic system will find a great potential in diagnosis and treatment integration in tumor treatments, and broaden the applications of PTT treatment.
A metal–polyphenol network coated nanotheranostic system for metastatic tumor treatments is developed. The theranostic system can inhibit primary tumor and suppress tumor metastasis effectively with combined photothermal and chemotherapy and the release of polyphenol. Moreover, the system shows superior imaging capability in computerized tomography and magnetic resonance imaging.
The MYC oncogene is overexpressed in hepatocellular carcinoma (HCC) and has been associated with widespread microRNA (miRNA) repression; however, the underlying mechanisms are largely unknown. Here, ...we report that the c‐Myc oncogenic transcription factor physically interacts with enhancer of zeste homolog 2 (EZH2), a core enzymatic unit of polycomb repressive complex 2 (PRC2). Furthermore, miR‐101, an important tumor‐suppressive miRNA in human hepatocarcinomas, is epigenetically repressed by PRC2 complex in a c‐Myc‐mediated manner. miR‐101, in turn, inhibits the expression of two subunits of PRC2 (EZH2 and EED), thus creating a double‐negative feedback loop that regulates the process of hepatocarcinogenesis. Restoration of miR‐101 expression suppresses multiple malignant phenotypes of HCC cells by coordinate repression of a cohort of oncogenes, including STMN1, JUNB, and CXCR7, and further increases expression of endogenous miR‐101 by inhibition of PRC2 activation. In addition, co‐overexpression of c‐Myc and EZH2 in HCC samples was closely associated with lower expression of miR‐101 (P < 0.0001) and poorer prognosis of HCC patients (P < 0.01). Conclusions: c‐Myc collaborates with EZH2‐containing PRC2 complex in silencing tumor‐suppressive miRNAs during hepatocarcinogenesis and provides promising therapeutic candidates for human HCC. (Hepatology 2014;59:1850–1863)
In daily monitoring of structures instrumented with long‐term structural health monitoring (SHM) systems, the acquired data is often corrupted with gross outliers due to hardware imperfection and/or ...electromagnetic interference. These unexpected spikes in data are not unusual and their existence may greatly influence the results of structural health evaluation and lead to false alarms. Hence, there is a high demand for executing data cleaning and data recovery, especially in harsh monitoring environment. In this paper, we propose a robust gross outlier removal method, termed Hankel‐structured robust principal component analysis (HRPCA), to remove gross outliers in the monitoring data of structural dynamic responses. Different from the deep‐learning‐based approaches that possess only outlier identification or anomaly classification ability, HRPCA is a rapid and integrated methodology for data cleaning, which enables outlier detection, outlier identification, and recovery of fault data. It capitalizes on the fundamental duality between the sparsity of the signal and the rank of the structured matrix. Using annihilating filter‐based fundamental duality, structural responses could be modeled as lying in a low‐dimensional subspace with additional Hankel structure; thus, the gross outliers could be represented as a sparse component. Then the outlier removal issue turns into a matrix factorization problem, which could be successfully solved by robust principal component analysis (RPCA). To validate the denoising capability of HRPCA, a laboratory experiment is first conducted on a five‐story building model where the reference clean signal is aware. Then real‐world monitoring data with varying degrees of outliers (e.g., single outlier, multiple outliers, and periodic outliers) collected from a cable‐stayed bridge and a high‐rise structure is used to further illustrate the efficiency of the proposed approach.
Circulating tumor DNA (ctDNA) isolated from peripheral blood has recently been shown to be an alternative source to detect gene mutations in primary tumors; however, most previous studies have ...focused on advanced stage cancers, and few have evaluated ctDNA detection in early-stage lung cancer. In the present study, blood and tumor samples were collected prospectively from 58 early-stage non-small lung cancer (NSCLC) patients (stages IA, IB, and IIA) and a targeted sequencing approach was used to detect somatic driver mutations in matched tumor DNA (tDNA) and plasma ctDNA. We identified frequent driver mutations in plasma ctDNA and tDNA in EGFR, KRAS, PIK3CA, and TP53, and less frequent mutations in other genes, with an overall study concordance of 50.4% and sensitivity and specificity of 53.8% and 47.3%, respectively. Cell-free (cfDNA) concentrations were found to be significantly associated with some clinical features, including tumor stage and subtype. Importantly, the presence of cfDNA had a higher positive predictive value than that of currently used protein tumor biomarkers. This study demonstrates the feasibility of identifying plasma ctDNA mutations in the earliest stage lung cancer patients via targeted sequencing, demonstrating a potential utility of targeted sequencing of ctDNA in the clinical management of NSCLC.
Highlights • The Ion PGM and AmpliSeq cancer panel can detect plasma ctDNA mutations from NSCLC. • ctDNA mutations in plasma are highly concordant to primary tumor tissue of NSCLC. • Our panel could ...be implemented for clinical use in a variety of advanced cancers.
Background
The monitoring of immunotherapies is still based on changes in the tumor size in imaging, with a long evaluation period and low sensitivity.
Purpose
To investigate the effectiveness of ...diffusion kurtosis imaging (DKI) and dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) in assessing the therapeutic efficacy of anti‐programmed death‐1 (PD‐1) therapy in a mouse triple negative breast cancer (TNBC) model.
Study Type
Prospective.
Animal Model
A total of 54 BALB/c mouse subcutaneous 4 T1 transplantation models of TNBC.
Field Strength/Sequence
A 3.0‐T; turbo spin echo (TSE) T2‐weighted imaging, DKI with seven b values (0, 500, 1000, 1500, 2000, 2500, and 3000 sec/mm2) and T1‐twist DCE acquisition series.
Assessment
DKI and DCE‐MRI parameters were evaluated by two radiologists independently. Regions of interest (ROIs) were drawn manually on the maximum cross‐sectional area of the lesion; care was taken to avoid necrotic areas. The tumor cell density, the CD45 and CD31 levels were analyzed by two pathologists.
Statistical Tests
The two‐tailed unpaired t‐test, Mann–Whitney U test, Fisher's exact test and Pearson correlation coefficient were performed. A P < 0.05 was considered statistically significant.
Results
The apparent diffusion coefficient (ADC), mean diffusivity (MD), Ktrans and Kep values were significantly different between the two groups at each time point after treatment. There were significant differences in the mean kurtosis (MK) and Ve values between the two groups at 5 and 10 days after treatment but no significant differences at 15 days (P = 0.317 and 0.183, respectively). The ADC and MD values were significantly correlated with tumor cell density (ADC, r = −0.833; MD, r = 0.890) and the CD45 level (ADC, r = 0.720; MD, r = 0.718). The Ktrans and Kep values were significantly correlated with the CD31 level (Ktrans, r = 0.820; Kep, r = 0.683).
Data Conclusion
DKI and DCE‐MRI could reflect the changes in tumor microstructure and tumor tissue vasculature after anti‐PD‐1 therapy, respectively.
Level of Evidence
1
Technical Efficacy
Stage 4.
Tumor vaccines represent a promising therapeutic approach, but thus far have achieved only limited success in the clinic. The major challenge is to find a means of overcoming inhibitory immune ...regulatory mechanisms and eliciting effective T-cell responses to antigens preferentially expressed by tumor cells. Here we show that the stimulatory capacity of dendritic cells (DCs) and the magnitude of adaptive immunity are critically regulated by the suppressor of cytokine signaling (SOCS) 1 in DCs. Silencing SOCS1 in antigen-presenting DCs strongly enhances antigen-specific anti-tumor immunity. Our findings indicate that SOCS1 represents an inhibitory mechanism for qualitatively and quantitatively controlling antigen presentation by DCs and the magnitude of adaptive immunity. This study has implications for understanding the regulation of antigen presentation and for developing more effective tumor vaccines by silencing the critical brake in antigen presentation.
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