Did you mean: cancel
-
International Journal of Molecular... Nov 2022Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric... (Review)
Review
Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development.
Topics: Humans; Neoplasms; Interleukin-1
PubMed: 36499246
DOI: 10.3390/ijms232314918 -
Cells Apr 2022The manufacture of efficacious CAR T cells represents a major challenge in cellular therapy. An important aspect of their quality concerns energy production and... (Review)
Review
The manufacture of efficacious CAR T cells represents a major challenge in cellular therapy. An important aspect of their quality concerns energy production and consumption, known as metabolism. T cells tend to adopt diverse metabolic profiles depending on their differentiation state and their stimulation level. It is therefore expected that the introduction of a synthetic molecule such as CAR, activating endogenous signaling pathways, will affect metabolism. In addition, upon patient treatment, the tumor microenvironment might influence the CAR T cell metabolism by compromising the energy resources. The access to novel technology with higher throughput and reduced cost has led to an increased interest in studying metabolism. Indeed, methods to quantify glycolysis and mitochondrial respiration have been available for decades but were rarely applied in the context of CAR T cell therapy before the release of the Seahorse XF apparatus. The present review will focus on the use of this instrument in the context of studies describing the impact of CAR on T cell metabolism and the strategies to render of CAR T cells more metabolically fit.
Topics: Glycolysis; Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Microenvironment
PubMed: 35563759
DOI: 10.3390/cells11091454 -
International Journal of Molecular... Apr 2021Chimeric antigen receptor (CAR) therapy is a promising modality for the treatment of advanced cancers that are otherwise incurable. During the last decade, different... (Review)
Review
Chimeric antigen receptor (CAR) therapy is a promising modality for the treatment of advanced cancers that are otherwise incurable. During the last decade, different centers worldwide have tested the anti-CD19 CAR T cells and shown clinical benefits in the treatment of B cell tumors. However, despite these encouraging results, CAR treatment has also been found to lead to serious side effects and capricious response profiles in patients. In addition, the CD19 CAR success has been difficult to reproduce for other types of malignancy. The appearance of resistant tumor variants, the lack of antigen specificity, and the occurrence of severe adverse effects due to over-stimulation of the therapeutic cells have been identified as the major impediments. This has motivated a growing interest in developing strategies to overcome these hurdles through CAR control. Among them, the combination of small molecules and approved drugs with CAR T cells has been investigated. These have been exploited to induce a synergistic anti-cancer effect but also to control the presence of the CAR T cells or tune the therapeutic activity. In the present review, we discuss opportunistic and rational approaches involving drugs featuring anti-cancer efficacy and CAR-adjustable effect.
Topics: B-Lymphocytes; Humans; Immunotherapy, Adoptive; Neoplasms
PubMed: 33919245
DOI: 10.3390/ijms22094320 -
Bioinformatics (Oxford, England) Jan 2022Mapping of chromatin accessibility landscapes in single-cells and the integration with gene expression enables a better understanding of gene regulatory mechanisms...
MOTIVATION
Mapping of chromatin accessibility landscapes in single-cells and the integration with gene expression enables a better understanding of gene regulatory mechanisms defining cell identities and cell-fate determination in development and disease. Generally, raw data generated from single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq) are deposited in repositories that are generally inaccessible due to lack of in-depth knowledge of computational programming.
RESULTS
We have developed ShinyArchR.UiO, an R-based shiny app, that facilitates scATAC-seq data accessibility and visualization in a user-friendly, interactive and open-source web interface. ShinyArchR.UiO is an application that can streamline collaborative efforts for interpretation of massive chromatin accessibility datasets and allow for open access data sharing for wider audiences.
AVAILABILITY AND IMPLEMENTATION
https://Github.com/EskelandLab/ShinyArchRUiO and a demo server with a hematopoietic tutorial dataset https://cancell.medisin.uio.no/ShinyArchR.UiO.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Chromatin Immunoprecipitation Sequencing; Chromatin; Single-Cell Analysis
PubMed: 34586377
DOI: 10.1093/bioinformatics/btab680 -
EClinicalMedicine Apr 2023The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants () who are receiving medical follow-up,...
Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.
BACKGROUND
The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants () who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.
METHODS
The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.
FINDINGS
Gynaecological cancers were more frequent than colorectal cancers in carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among carriers undergoing colonoscopy surveillance, particularly carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.
INTERPRETATION
In carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome.
FUNDING
We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.
PubMed: 37181409
DOI: 10.1016/j.eclinm.2023.101909 -
Hereditary Cancer in Clinical Practice Oct 2023The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1,... (Review)
Review
The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
PubMed: 37821984
DOI: 10.1186/s13053-023-00263-3 -
The Journal of Biological Chemistry Jul 2023Chimeric antigen receptor (CAR) T-cell therapy has had considerable success in the treatment of B-cell malignancies. Targeting the B-lineage marker CD19 has brought...
Chimeric antigen receptor (CAR) T-cell therapy has had considerable success in the treatment of B-cell malignancies. Targeting the B-lineage marker CD19 has brought great advances to the treatment of acute lymphoblastic leukemia and B-cell lymphomas. However, relapse remains an issue in many cases. Such relapse can result from downregulation or loss of CD19 from the malignant cell population or expression of alternate isoforms. Consequently, there remains a need to target alternative B-cell antigens and diversify the spectrum of epitopes targeted within the same antigen. CD22 has been identified as a substitute target in cases of CD19-negative relapse. One anti-CD22 antibody-clone m971-targets a membrane-proximal epitope of CD22 and has been widely validated and used in the clinic. Here, we have compared m971-CAR with a novel CAR derived from IS7, an antibody that targets a central epitope on CD22. The IS7-CAR has superior avidity and is active and specific against CD22-positive targets, including B-acute lymphoblastic leukemia patient-derived xenograft samples. Side-by-side comparisons indicated that while IS7-CAR killed less rapidly than m971-CAR in vitro, it remains efficient in controlling lymphoma xenograft models in vivo. Thus, IS7-CAR presents a potential alternative candidate for the treatment of refractory B-cell malignancies.
Topics: Humans; Antigens, CD19; Epitopes; Immunotherapy, Adoptive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Chimeric Antigen; Recurrence; Sialic Acid Binding Ig-like Lectin 2
PubMed: 37269947
DOI: 10.1016/j.jbc.2023.104883 -
Nature Communications Sep 2023γδ T cells play a pivotal role in protection against various types of infections and tumours, from early childhood on and throughout life. They consist of several...
γδ T cells play a pivotal role in protection against various types of infections and tumours, from early childhood on and throughout life. They consist of several subsets characterised by adaptive and innate-like functions, with Vγ9Vδ2 being the largest subset in human peripheral blood. Although these cells show signs of cytotoxicity, their modus operandi remains poorly understood. Here we explore, using live single-cell imaging, the cytotoxic functions of γδ T cells upon interactions with tumour target cells with high temporal and spatial resolution. While γδ T cell killing is dominated by degranulation, the availability of lytic molecules appears tightly regulated in time and space. In particular, the limited co-occurrence of granzyme B and perforin restrains serial killing of tumour cells by γδ T cells. Thus, our data provide new insights into the cytotoxic arsenal and functions of γδ T cells, which may guide the development of more efficient γδ T cell based adoptive immunotherapies.
Topics: Child, Preschool; Humans; Antineoplastic Agents; Perforin; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell, gamma-delta; Cytotoxicity, Immunologic
PubMed: 37758698
DOI: 10.1038/s41467-023-41634-7