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Frontiers in Oncology 2019Development of chimeric antigen receptor (CAR)-modified T cells for the treatment of T-lineage leukemia and lymphoma has encountered several unique challenges. The most... (Review)
Review
Development of chimeric antigen receptor (CAR)-modified T cells for the treatment of T-lineage leukemia and lymphoma has encountered several unique challenges. The most widely expressed tumor antigen targets for malignant T cells are often also expressed on non-malignant T cells. Transducing T cells with CARs targeted to these shared antigens can therefore promote over-activation or fratricide of CAR T cells, reducing their therapeutic potency. If fratricide is resolved, clinical CAR T cell activity may eliminate normal T-cell subsets and cause temporary immunosuppression. In this review, we summarize the preclinical development of CAR-based therapies for T-cell malignancies and discuss strategies to minimize toxicities associated with on-target fratricide and off-tumor activity.
PubMed: 30891427
DOI: 10.3389/fonc.2019.00126 -
Rambam Maimonides Medical Journal Sep 2018Cancer patients have a pro-thrombotic state attributed to the ability of cancer cells to activate the coagulation system and interact with hemostatic cells, thus tilting...
Cancer patients have a pro-thrombotic state attributed to the ability of cancer cells to activate the coagulation system and interact with hemostatic cells, thus tilting the balance between pro- and anticoagulants. Mechanisms underlying the coagulation system activation involve tumor cells, endothelial cells, platelets, and white blood cells. Anti-cancer therapies, including anti-angiogenic drugs, significantly increase the risk of thrombosis during treatment. Along with the role of coagulation proteins in the hemostatic system, these proteins also serve as growth factors to the tumor. Heparanase is a pro-angiogenic and pro-metastatic protein. Our previous studies have demonstrated that it enhances tissue factor (TF) activity and is present at high levels in tumor cells and patients' blood. Strategies to attenuate heparanase effects by heparin mimetics or peptides interrupting the TF-heparanase interaction are good candidates to attenuate tumor growth and thrombotic manifestations.
PubMed: 30180930
DOI: 10.5041/RMMJ.10349 -
Medical Sciences (Basel, Switzerland) Feb 2023Brenner tumors (BTs) are surface-epithelial stromal cell tumors that are categorized by the World Health Organization as benign, borderline, and malignant. Due to the... (Review)
Review
Brenner tumors (BTs) are surface-epithelial stromal cell tumors that are categorized by the World Health Organization as benign, borderline, and malignant. Due to the rarity of BTs, the published literature on these tumors is comprised primarily of case reports and small retrospective studies. We performed a pathology database review spanning the last ten years at our institution revealing nine reported benign BTs. We collected the clinical and pathological data of patients associated with those BTs, describing the clinical presentation and imaging results, and assessing the possible risk factors associated with them. The average age at diagnosis was 58 years. BTs were discovered incidentally in 7/9 cases. The tumor was multifocal and bilateral in 1/9 cases and ranged in size from 0.2 cm to 7.5 cm. Associated Walthard rests were found in 6/9 cases and transitional metaplasia of surface ovarian and/or tubal epithelium was found in 4/9 cases. One patient had an associated mucinous cystadenoma in the ipsilateral ovary. Another patient had an associated mucinous cystadenoma in the contralateral ovary. In conclusion, we found that Walthard rests and transitional metaplasia are common findings in association with BTs. Additionally, pathologists and surgeons need to be aware of the association between mucinous cystadenomas and BTs.
Topics: Female; Humans; Middle Aged; Cystadenoma, Mucinous; Ovarian Neoplasms; Retrospective Studies; Brenner Tumor; Metaplasia
PubMed: 36810485
DOI: 10.3390/medsci11010018 -
Frontiers in Genetics 2022Cancer biomarkers are a promising tool for cancer detection, personalization of therapy, and monitoring of treatment response or recurrence. "Liquid biopsy" commonly... (Review)
Review
Cancer biomarkers are a promising tool for cancer detection, personalization of therapy, and monitoring of treatment response or recurrence. "Liquid biopsy" commonly refers to minimally invasive or non-invasive sampling of a bodily fluid (i.e., blood, urine, saliva) for detection of cancer biomarkers such as circulating tumor cells or cell-free tumor DNA (ctDNA). These methods offer a means to collect frequent tumor assessments without needing surgical biopsies. Despite much progress with blood-based liquid biopsy approaches, there are limitations-including the limited amount of blood that can be drawn from a person and challenges with collecting blood samples at frequent intervals to capture ctDNA biomarker kinetics. These limitations are important because ctDNA is present at extremely low levels in plasma and there is evidence that measuring ctDNA biomarker kinetics over time can be useful for clinical prediction. Additionally, blood-based assays require access to trained phlebotomists and often a trip to a healthcare facility. In contrast, urine is a body fluid that can be self-collected from a patient's home, at frequent intervals, and mailed to a laboratory for analysis. Multiple reports indicate that fragments of ctDNA pass from the bloodstream through the kidney's glomerular filtration system into the urine, where they are known as trans-renal ctDNA (TR-ctDNA). Accumulating studies indicate that the limitations of blood based ctDNA approaches for cancer can be overcome by measuring TR-ctDNA. Here, we review current knowledge about TR-ctDNA in urine as a cancer biomarker approach, and discuss its clinical potential and open questions in this research field.
PubMed: 35571046
DOI: 10.3389/fgene.2022.879108 -
Molecular and Clinical Oncology Jan 2017Brenner tumor is a rare type tumor, which mainly develops in the ovaries and rarely in the adnexal region and urinary system. To the best of our knowledge, only 5 cases...
Brenner tumor is a rare type tumor, which mainly develops in the ovaries and rarely in the adnexal region and urinary system. To the best of our knowledge, only 5 cases of testicular Brenner tumor have been reported to date. In this report, we present the case of a 55-year-old patient who noted a swelling of the right scrotum for ~20 days. The clinical suspicion was an epididymal cyst. However, following surgical resection and subsequent pathological examination, the mass was diagnosed as a testicular Brenner tumor. A supplementary review of previously published cases and literature is also presented. The aim of this report is to help elucidate this disease and reduce the rate of clinical and pathological misdiagnosis.
PubMed: 28123743
DOI: 10.3892/mco.2016.1083 -
Trends in Immunology Mar 2023T cell subsets adapt and rewire their metabolism according to their functions and surrounding microenvironment. Whereas naive T cells rely on mitochondrial metabolic... (Review)
Review
T cell subsets adapt and rewire their metabolism according to their functions and surrounding microenvironment. Whereas naive T cells rely on mitochondrial metabolic pathways characterized by low nutrient requirements, effector T cells induce kinetically faster pathways to generate the biomass and energy needed for proliferation and cytokine production. Recent findings support the concept that alterations in metabolism also affect the epigenetics of T cells. In this review we discuss the connections between T cell metabolism and epigenetic changes such as histone post-translational modifications (PTMs) and DNA methylation, as well as the 'extra-metabolic' roles of metabolic enzymes and molecules. These findings collectively point to a new group of potential therapeutic targets for the treatment of T cell-dependent autoimmune diseases and cancers.
Topics: Humans; Epigenesis, Genetic; Histones; DNA Methylation; Neoplasms; Protein Processing, Post-Translational; T-Lymphocytes; Tumor Microenvironment
PubMed: 36774330
DOI: 10.1016/j.it.2023.01.002 -
Cell Research Jan 2017Approximately 12% of all cancers worldwide are associated with viral infections. To date, eight viruses have been shown to contribute to the development of human... (Review)
Review
Approximately 12% of all cancers worldwide are associated with viral infections. To date, eight viruses have been shown to contribute to the development of human cancers, including Epstein-Barr virus (EBV), Hepatitis B and C viruses, and Human papilloma virus, among others. These DNA and RNA viruses produce oncogenic effects through distinct mechanisms. First, viruses may induce sustained disorders of host cell growth and survival through the genes they express, or may induce DNA damage response in host cells, which in turn increases host genome instability. Second, they may induce chronic inflammation and secondary tissue damage favoring the development of oncogenic processes in host cells. Viruses like HIV can create a more permissive environment for cancer development through immune inhibition, but we will focus on the previous two mechanisms in this review. Unlike traditional cancer therapies that cannot distinguish infected cells from non-infected cells, immunotherapies are uniquely equipped to target virus-associated malignancies. The targeting and functioning mechanisms associated with the immune response can be exploited to prevent viral infections by vaccination, and can also be used to treat infection before cancer establishment. Successes in using the immune system to eradicate established malignancy by selective recognition of virus-associated tumor cells are currently being reported. For example, numerous clinical trials of adoptive transfer of ex vivo generated virus-specific T cells have shown benefit even for established tumors in patients with EBV-associated malignancies. Additional studies in other virus-associated tumors have also been initiated and in this review we describe the current status of immunotherapy for virus-associated malignancies and discuss future prospects.
Topics: Animals; Cancer Vaccines; Clinical Trials as Topic; Humans; Immunotherapy; Neoplasms; Viruses
PubMed: 28008927
DOI: 10.1038/cr.2016.153 -
Cancers Oct 2019This series of 25 articles (22 original articles, 3 reviews) is presented by international leaders in bioinformatics and biostatistics [...].
This series of 25 articles (22 original articles, 3 reviews) is presented by international leaders in bioinformatics and biostatistics [...].
PubMed: 31652939
DOI: 10.3390/cancers11111630 -
Frontiers in Cell and Developmental... 2022Osteosarcoma (OS) is a pediatric malignant bone tumor that predominantly affects adolescent and young adults. It has high risk for relapse and over the last four decades... (Review)
Review
Osteosarcoma (OS) is a pediatric malignant bone tumor that predominantly affects adolescent and young adults. It has high risk for relapse and over the last four decades no improvement of prognosis was achieved. It is therefore crucial to identify new drug candidates for OS treatment to combat drug resistance, limit relapse, and stop metastatic spread. Two acquired hallmarks of cancer cells, mitochondria-related regulated cell death (RCD) and metabolism are intimately connected. Both have been shown to be dysregulated in OS, making them attractive targets for novel treatment. Promising OS treatment strategies focus on promoting RCD by targeting key molecular actors in metabolic reprogramming. The exact interplay in OS, however, has not been systematically analyzed. We therefore review these aspects by synthesizing current knowledge in apoptosis, ferroptosis, necroptosis, pyroptosis, and autophagy in OS. Additionally, we outline an overview of mitochondrial function and metabolic profiles in different preclinical OS models. Finally, we discuss the mechanism of action of two novel molecule combinations currently investigated in active clinical trials: metformin and the combination of ADI-PEG20, Docetaxel and Gemcitabine.
PubMed: 36072341
DOI: 10.3389/fcell.2022.948097 -
Journal For Immunotherapy of Cancer Jan 2023Cell therapies for solid tumors are thwarted by the hostile tumor microenvironment (TME) and by heterogeneous expression of tumor target antigens. We address both...
BACKGROUND
Cell therapies for solid tumors are thwarted by the hostile tumor microenvironment (TME) and by heterogeneous expression of tumor target antigens. We address both limitations with a novel class of chimeric antigen receptors based on plant lectins, which recognize the aberrant sugar residues that are a 'hallmark' of both malignant and associated stromal cells. We have expressed in T cells a modified lectin from banana, H84T BanLec, attached to a chimeric antigen receptor (H84T-CAR) that recognizes high-mannose (asparagine residue with five to nine mannoses). Here, we tested the efficacy of our novel H84T CAR in models of pancreatic ductal adenocarcinoma (PDAC), intractable tumors with aberrant glycosylation and characterized by desmoplastic stroma largely contributed by pancreatic stellate cells (PSCs).
METHODS
We transduced human T cells with a second-generation retroviral construct expressing the H84T BanLec chimeric receptor, measured T-cell expansion, characterized T-cell phenotype, and tested their efficacy against PDAC tumor cells lines by flow cytometry quantification. In three-dimensional (3D) spheroid models, we measured H84T CAR T-cell disruption of PSC architecture, and T-cell infiltration by live imaging. We tested the activity of H84T CAR T cells against tumor xenografts derived from three PDAC cell lines. Antitumor activity was quantified by caliper measurement and bioluminescence signal and used anti-human vimentin to measure residual PSCs.
RESULTS
H84T BanLec CAR was successfully transduced and expressed by T cells which had robust expansion and retained central memory phenotype in both CD4 and CD8 compartments. H84T CAR T cells targeted and eliminated PDAC tumor cell lines. They also disrupted PSC architecture in 3D models in vitro and reduced total tumor and stroma cells in mixed co-cultures. H84T CAR T cells exhibited improved T-cell infiltration in multicellular spheroids and had potent antitumor effects in the xenograft models. We observed no adverse effects against normal tissues.
CONCLUSIONS
T cells expressing H84T CAR target malignant cells and their stroma in PDAC tumor models. The incorporation of glycan-targeting lectins within CARs thus extends their activity to include both malignant cells and their supporting stromal cells, disrupting the TME that otherwise diminishes the activity of cellular therapies against solid tumors.
Topics: Humans; Musa; Lectins; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; T-Lymphocytes; Receptors, Chimeric Antigen; Tumor Microenvironment
PubMed: 36653070
DOI: 10.1136/jitc-2022-005891