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Mass Spectrometry Approaches for Identification and Quantitation of Therapeutic Monoclonal Antibodies in the Clinical Laboratory.

Therapeutic monoclonal antibodies (MAbs) are an important class of drugs used to treat diseases ranging from autoimmune disorders to B cell lymphomas to other rare conditions thought to be untreatable in the past. Many advances have been made in the characterization of immunoglobulins as a result of pharmaceutical companies investing in technologies that allow them to better understand MAbs during the development phase. Mass spectrometry is one of the new advancements utilized extensively by pharma to analyze MAbs and is now beginning to be applied in the clinical laboratory setting. The rise

Machine learning in onco-pharmacogenomics: a path to precision medicine with many challenges.

Over the past two decades, Next-Generation Sequencing (NGS) has revolutionized the approach to cancer research. Applications of NGS include the identification of tumor specific alterations that can influence tumor pathobiology and also impact diagnosis, prognosis and therapeutic options. Pharmacogenomics (PGx) studies the role of inheritance of individual genetic patterns in drug response and has taken advantage of NGS technology as it provides access to high-throughput data that can, however, be difficult to manage. Machine learning (ML) has recently been used in the life sciences to discover

Long-term survival in multiple myeloma.

Key clinical messageThe survival of multiple myeloma patients has improved very significantly over the last decade. Still median overall survival is inferior to 5 years. A small proportion of patients survive longer than 10 years. In this paper we discuss four cases illustrating the nonhomogeneous clinical presentation and evolution of this subset of patients. Surprisingly, these long survivors do not always have deep responses and some require frequent treatments, which include autologous stem cell transplantation and novel drugs. The authors discuss several aspects of these clinical historie

Up-regulation of bone marrow stromal protein 2 (BST2) in breast cancer with bone metastasis.

BackgroundBone metastases are frequent complications of breast cancer. Recent literature implicates multiple chemokines in the formation of bone metastases in breast cancer. However, the molecular mechanism of metastatic bone disease in breast cancer remains unknown. We have recently made the novel observation of the BST2 protein expression in human breast cancer cell lines. The purpose of our present study is to investigate the expression and the role of BST2 in bone metastatic breast cancer.MethodscDNA microarray analysis was used to compare the BST2 gene expression between a metastatic to b

Immunotherapy for pediatric solid tumors: overcoming biological barriers through rational multimodal combinations.

Pediatric solid tumors remain among the most treatment-refractory childhood malignancies, defined by biological features that have largely resisted the immunotherapeutic advances transforming adult oncology. Exceptionally low tumor mutational burden, sparse neoantigen landscapes, and profoundly immunosuppressive tumor microenvironments collectively undermine the T cell-dependent mechanisms on which most current immunotherapies depend. Yet the field is undergoing a meaningful shift. Anti-GD2 monoclonal antibodies have established a survival benchmark in high-risk neuroblastoma, and next-generat

Keyword Index for Volume 111

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NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma.

Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 × 10(9) engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels.

The biogenesis and biological function of PIWI-interacting RNA in cancer.

Small non-coding RNAs (ncRNAs) are vital regulators of biological activities, and aberrant levels of small ncRNAs are commonly found in precancerous lesions and cancer. PIWI-interacting RNAs (piRNAs) are a novel type of small ncRNA initially discovered in germ cells that have a specific length (24-31 nucleotides), bind to PIWI proteins, and show 2'-O-methyl modification at the 3'-end. Numerous studies have revealed that piRNAs can play important roles in tumorigenesis via multiple biological regulatory mechanisms, including silencing transcriptional and posttranscriptional gene processes and a

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… The precursors of piRNAs are derived from tandem repeat sequences called piRNA clusters and form a mature piRNA/PIWI complex via two routes dependent or independent “Ping-Pong” amplification pathways [ 2 ]. piRNAs were initially identified as highly expressed in germline cells and able to silence transposons …

Exploring CAR-PBMCs: A Novel Strategy Against EGFR-Positive Tumor Cells.

Background: Chimeric antigen receptor (CAR) T cell therapy has shown significant promise in treating hematological malignancies, yet its application in solid tumors, particularly those expressing the epidermal growth factor receptor (EGFR), remains limited. This study investigates the potential of CAR-engineered peripheral blood mononuclear cells (PBMCs) as a novel adoptive cell therapy against EGFR-positive cancers. Methods: Lentiviral transduction at an MOI of 50 was performed to generate specific anti-EGFR second generation CAR-effector cells. The transduced PBMCs were stimulated with cytok

Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia.

Epigenetic alteration has been proposed to give rise to numerous classic hallmarks of cancer. Impaired DNA methylation plays a central role in the onset and progression of several types of malignancies, and DNA methylation is mediated by DNA methyltransferases (DNMTs) consisting of DNMT1, DNMT3A, and DNMT3B. DNMTs are frequently implicated in the pathogenesis and aggressiveness of acute myeloid leukaemia (AML) patients. In this review, we describe and discuss the oncogenic roles of DNMT1, DNMT3A, and DNMT3B in AML. The clinical response predictive roles of DNMTs in clinical trials utilising hy

Confirmatory Trials in the Evaluation of Anticancer Medicinal Products in Man--PFS2: A Measure of Therapeutic Action-At-A-Distance.

Overall survival (OS) has emerged as the definitive regulatory "be-all, end-all" for the demonstration of benefit in cancer clinical trials. The reason and the rationale for why this is so are easily appreciated: literally a "test of time," OS is a seemingly unambiguous, agenda-free end point, independent of bias-prone variables such as the frequency and methods of assessment, clinical evaluation, and the definition of progression. However, by general consensus, OS is an imperfect end point for several reasons: First, it may often be impractical because of the length, cost, and the size of cli

Abstracts of the 12th European Cytogenomics Conference 2019 : Salzburg, Austria. 6-9 July 2019

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Chimeric Antigen Receptor Design and Efficacy in Ovarian Cancer Treatment.

Our increased understanding of tumour biology gained over the last few years has led to the development of targeted molecular therapies, e.g., vascular endothelial growth factor A (VEGF-A) antagonists, poly[ADP-ribose] polymerase 1 (PARP1) inhibitors in hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2 mutants), increasing survival and improving the quality of life. However, the majority of ovarian cancer (OC) patients still do not have access to targeted molecular therapies that would be capable of controlling their disease, especially resistant or relapsed. Chimeric antigen rece

Генетические причины непатогенных штаммов Pseudomonas syringae pv. actinidiae в киви-садах.

Бактериальная канцерозная болезнь стала наибольшей угрозой для выращивания и производства киви. Мономорфная подпопуляция Pseudomonas syringae pv. actinidiae biovar 3 (Psa3) отвечает за пандемию по всему миру. В пандемической подпопуляции и других подпопуляциях Psa3, вызывающих эпидемии в Китае, обнаружена разнообразие в патогенности. Однако генетические основы еще не были раскрыты. В данном исследовании 117 изолятов Psa3 были идентифицированы с помощью Psa- и P. Psa3-специфических праймеров и оценены по патогенности. Три изолата G4, G40 и S2 не патогенны для киви и не вызывают гиперчувствитель

Patient-Derived Organoids as a Promising Tool for Multimodal Management of Sarcomas.

The management of sarcomas, a diverse group of cancers arising from connective tissues, presents significant challenges due to their heterogeneity and limited treatment options. Patient-derived sarcoma organoids (PDSOs) have emerged as a promising tool in the multimodal management of sarcomas, offering unprecedented opportunities for personalized medicine and improved treatment strategies. This review aims to explore the potential of PDSOs as a promising tool for multimodal management of sarcomas. We discuss the establishment and characterization of PDSOs, which realistically recapitulate the

Репрессии на цикле синергии со стороны HDAC/EZH2 H3K27-altered диффузная средняя глиома.

Diffuse midline glioma (DMG) — агрессивная хитрость под воздействием H3K27M онкохистоуна, приводящая к глобальному эпигенетическому регулированию и ограниченной эффективности одноагентной эпигенетической терапии. Ранее мы наблюдали клиническую выгоду от ингибитора HDAC/EZH2, но механистическая основа была неясной. Для принятия ответных мер в связи с наркотиками и проведения функциональных анализов использовалась группа культур ДИМ-глиомы стволовых клеток (ГНК) от опухолей головного мозга и спинного мозга, при этом репрезентативные модели были дополнительно проанализированы на предмет транскрип

A Case Report Supporting the Use of Teclistamab in Multiple Myeloma With CNS Involvement.

Central nervous system involvement in multiple myeloma (MM-CNS) is a condition with poor prognosis and no clear treatment options. Standard regimens, including proteasome inhibitors (PIs) and immunomodulatory (IMiD) agents, provide minimal benefit in this setting, highlighting the need for novel therapies. Teclistamab, a bispecific T-cell engager (BiTE) targeting B-cell maturation agent (BCMA) and CD3, has demonstrated robust systemic activity in heavily pretreated MM but its role in CNS disease remains undefined, as patients with CNS involvement have been excluded from pivotal trials. We pres

The beginning of a new therapeutic era in acute myeloid leukemia.

In the field of AML, the early 2000s were shaped by the advent of novel molecular biology technologies including high-throughput sequencing that improved prognostic classification, response evaluation through the quantification of minimal residual disease, and the launch of research on targeted therapies. Our knowledge of leukemogenesis, AML genetic diversity, gene-gene interactions, clonal evolution, and treatment response assessment has also greatly improved. New classifications based on chromosomal abnormalities and gene mutations are now integrated on a routine basis. These considerable ef

A same-day assay predicts apoptotic response to combined BCL-2 and MCL-1 BH3-mimetic targeting in multiple myeloma cells.

Recent advances in treatment options for multiple myeloma (MM) have positive impact on patient survival. However, there is a short fall of rapid and reliable assays that can predict patient response to novel agents. The anti-apoptotic proteins B-cell lymphoma-2 (BCL-2) and myeloid cell leukaemia-1 (MCL-1), are necessary for MM survival, although most myelomas are more dependent on MCL-1. BCL-2 inhibition alone yields significant cytotoxicity in only a minority of cases, therefore targeting both proteins simultaneously, is a therapeutic option. Venetoclax and S63845 are BCL-2 and MCL-1 targetin

Heat shock protein 90 and role of its chemical inhibitors in treatment of hematologic malignancies.

Heat shock protein 90 (Hsp90) is a conserved and constitutively expressed molecular chaperone and it has been shown to stabilize oncoproteins and facilitate cancer development. Hsp90 has been considered as a therapeutic target for cancers and three classes of Hsp90 inhibitors have been developed: (1) benzoquinone ansamycin and its derivatives, (2) radicicol and its derivates, and (3) small synthetic inhibitors. The roles of these inhibitors in cancer treatment have been studied in laboratories and clinical trials, and some encouraging results have been obtained. Interestingly, targeting of Hsp