Tom Jones’ Post

Rachel Watkins is Director of Experimental Biology at CoSyne Therapeutics, a company working on creating a platform for drug discovery in under-served brain diseases, based on high-quality scientific data integrated with AI and machine learning. We all know the saying ‘garbage in, garbage out’ so CoSyne have concentrated on generating the highest quality, clinically relevant data for their platform. Focusing initially on astroglial diseases, including aggressive brain cancers, CoSyne aim to develop a model that can aid drug discovery for brain diseases and beyond. Working from a biobank of patient-derived tumour cell lines, cells are grown in 3D culture to mimic tumour conditions as closely as possible e.g. hypoxia gradient. These cells are then characterised through whole-genome sequencing, single-cell transcriptomics and CRISPRi screens and these data used to power AI generated cellular simulations in order to identify biomarker / target pairings. To verify their platform’s efficiency CoSyne have identified biomarker/target pairings already established in the literature as well as many novel targets. This work has shown that the platform is working well and CoSyne are currently looking at re-purposing phase I safe but de-prioritised therapeutics towards new indications to accelerate the path of new treatments for patients in need. Rachel will be speaking at Drug Discovery 2024 on Thursday 3 October in the track ‘Target discovery and disease modelling’. Register now to catch her talk at Drug Discovery 2024: https://lnkd.in/ePmtmfN9 #braincancer #CRISPR #braindisease #singlecellsequencing #singlecell #therapeutics #cancer #tumor #braintumor #genomics #wholegenomesequencing #transcriptomics

Engineered Peptides Stimulate Antitumor Immune Responses in Mice Researchers have designed a new method for developing immunotherapy drugs using engineered peptides to elicit a natural immune response inside the body. More specifically, they showed, in antigen presenting cells, that “the hydrophobicity, electrostatic charge, and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress.” In preclinical models of locally advanced and metastatic breast cancer, this method improved tumor control and prolonged survival, both as a monotherapy and in combination with immune checkpoint inhibitors. This work is published in Nature Biomedical Engineering in the paper, “Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells.” Rather than using an external compound to initiate a response, or harvesting and modifying immune cells for cell therapies, the peptide serves as a messenger to activate specific signaling pathways in immune cells to boost their performance. More specifically, one of the three engineered polypeptides activated “two major intracellular DNA-sensing pathways (cGAS–STING (for cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells.” The authors noted that, in mouse models of locally advanced and metastatic breast cancers, the polypeptides led to “potent DNA-sensor-mediated antitumor responses when intravenously given as monotherapy or with immune checkpoint inhibitors.” These findings open a whole new avenue for developing immunotherapy drugs. By using designed polypeptides, potently activate immune signaling pathways to enhance antitumor responses can be achieved. Additionally, since these are naturally derived agents, the toxicity profile would be expected to be significantly better than with synthetic compounds. #opportunities #strategy #programming #design #team #research #data #health #development #collaboration #projects #testing #immunotherapy #cancer #technology #biotechnology #healthcare #medicine #oncology #precisionmedicine #liquidbiopsy #rna #dna #venturecapital #startup #immunooncology #tcells #innovation #growth #tech #lifesciences #biopharma #oncodxrx

In vivo CAR-T cell generation --> Taking the field to a whole new level! LNPs are conjugated on their surface with antibodies targeting panT-cell markers (CD3, CD5, CD7) and injected intravenously. Targeted delivery of the mRNA payload occurs in vivo and circulating, functional CAR-Ts are generated directly in the patient avoiding leukapheresis and ex-vivo T-cell expansion. Usually i.v. injection of LNPs suffers from liver trapping due to the presence of Kupffer cells, in this work the authors show extra-hepatic delivery of their targeted ionizable lipid nanoparticles (LNPs) yielding to active CAR-T cells. Hats off to Margaret Billingsley and Michael J Mitchell 👏

Exciting new research by Setsuko Mise-Omata and colleagues highlights the potential of SOCS3 deletion in T cells to enhance anti-tumor responses! The study shows that removing SOCS3 in effector T cells reprograms the traditionally pro-tumorigenic cytokine IL-6 into an anti-tumor agent. This transformation boosts the differentiation of exhausted progenitor T cells into highly effective effector cells. A key finding is the improvement in mitochondrial fitness, with increased mitochondrial membrane potential and reactive oxygen species (ROS) levels. This metabolic shift leads to enhanced glycolysis and a remarkable anti-tumor immune response. Additionally, the SOCS3 knockdown in human CAR-T cells demonstrated significant improvements in anti-tumor activity, suggesting promising therapeutic implications. - I am currently working on integrating OCR monitoring into the CAR-T cell manufacturing process. My goal is to explore the potential of selecting CAR-T cells with high OCR to enhance their therapeutic effectiveness. I am seeking collaborators for this research proposal. If you are interested in this project, please feel free to reach out to me. #CancerResearch #Immunotherapy #TCellTherapy #SOCS3 #IL6 #MetabolicReprogramming #MitochondrialFitness #OxygenConsumption #Glycolysis #RegenerativeMedicine #CellTherapy #Oncology - ref. SOCS3 deletion in effector T cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine (https://lnkd.in/gjkmQPkQ)

𝙄𝙣 𝙫𝙞𝙫𝙤 𝗚𝗲𝗻𝗲𝗿𝗮𝘁𝗶𝗼𝗻 𝗼𝗳 𝗖𝗔𝗥-𝗧 𝗖𝗲𝗹𝗹𝘀 🤩 Currently, 12 therapies based on CAR-T have been approved, with 6 approved in the USA by the FDA and another 6 approved in China by the NMPA. The main drawbacks of CAR-T engineering lie in ex-vivo transduction, which requires high production costs, time-consuming procedures, and patient-specific manufacturing. In our previous post (https://rb.gy/brwnnn), we presented an article focusing on mRNA-LNP-derived CAR-T cells. Today, we would like to go one step further towards the future of CAR-T cell engineering! 🔭 Have a look this article by Margaret Billingsley and colleagues presenting a complete study on 𝑖𝑛 𝑣𝑖𝑣𝑜 generation of CAR-T cells! What is interesting about this work: 1. mRNA-LNPs are functionalized with Antibodies (Ab) to target pan-T cell markers (CD3, CD5, CD7). 2. The Ab-LNPs described in this work demonstrate 𝑖𝑛 𝑣𝑖𝑣𝑜 extrahepatic delivery, yielding functional circulating CAR-T cells. 3. Cytokine levels in treated mice showed transient dose-dependent elevation in serum, supporting the safety and ability of Ab-LNPs to be dosed repeatedly. 4. The 𝑖𝑛 𝑣𝑖𝑣𝑜 engineered CD19-CAR derived from anti-CD3-LNP led to 90% depletion of B cells at 36 hours post injection, demonstrating therapeutic efficacy for treating B cell cancers. We are looking forward to seeing what this new generation CAR-T technology will achieve for the treatment of liquid and solid tumors! We are seeking collaborators to explore this groundbreaking, novel technology-->get in touch with our BD team! Congyu (Chloe) Wu and Cesare Di Nitto 🤝 #CARTCells #CancerResearch #Immunotherapy #Biotech #Innovation #Healthcare #Oncology #MedicalResearch #GeneTherapy #CancerTreatment #Biotechnology #FutureOfMedicine #MedicalInnovation #TherapeuticDevelopment #CollaborativeResearch #NextGenTherapies

Researchers have demonstrated that a functional #precisionmedicine approach combining #AI artificial intelligence, #DNA sequencing and #drug sensitivity testing could feasibly help tackle hard-to-treat cancers regardless of their type, including among children with relapsed solid tumors and blood-based malignancies. The process, being developed by First Ascent Biomedical, showed promise in a small study published this week in Nature Medicine. It begins by collecting, culturing and analyzing tumor cells from each individual patient and then exposing those samples to more than 10 dozen FDA-approved drugs, including some that are aimed at cancer and some that are not, such as statins for high cholesterol. Picking out the best performers and potential combinations takes about a week. Out of six patients who received these guided therapies, five showed strong improvements in their progression-free survival—this time outpacing the periods they had spent cancer-free, before the disease returned after at least two initial treatments.

It gives me immense pleasure to share the recent copyright granted on "Protocol for Compilation of Differentially Regulated Molecules for Esophageal Squamous Cell Cancer"  It describes a protocol outline with a vital methodology for identifying significant molecular alterations, especially differentially regulated genes (DEGs) or differentially expressed proteins (DEMs) in cancer, which paves the way for the development of innovative diagnostic and therapeutic strategies for esophageal squamous cell carcinoma (ESCC). By employing advanced genomic and proteomic techniques, this protocol enables researchers to uncover epigenetic alterations, and abnormal gene or protein expression, which are pivotal in ESCC pathogenesis. The detailed molecular profiling steps facilitated by this protocol not only enhance our understanding of the disease mechanisms but also identify potential biomarkers for early detection and disease monitoring. The data generated through this process would help in providing a set of DEGs/DEMs that could be useful not only for the discrimination between ESCC vs. normal tissues but also for the development of targeted therapy is for ESCC. Therefore, this protocol represents a cornerstone step in ongoing efforts from our group to combat ESCC by identifying DEGs/DEMs to translate research from bench to bedside, ultimately aiming to enhance diagnostic/prognostic accuracy and therapeutic efficacy for ESCC patients. Consequently, this approach holds promise for improving patient outcomes through more precise and personalized treatment regimens. Furthermore, this protocol can be extrapolated to other diseases and malignancies as well. I am thankful to my colleague, Dr. Manoj K Kashyap, who was the guiding figure to make this idea come into reality. We hope that this protocol makes a significant contribution to the scientific community. #copyright #cancercells #ESSC #DEGs #DEMs #targetteddrugdelivery #medicine #therapeutics #diagnostic #translationalresearch #STEM #amityuniversity

Happy new year!   I imagine many of you are just returning from the holidays, eager to catch up on the latest news and publications. So, please be sure to check out our newest preprint. In this study, led by our very talented postdoc, Susanta, we uncover a pivotal role for the Ribosome Quality Control (RQC) mechanism in safeguarding cells against the toxicity induced by 5-Fluorouracil (5FU), a key component in cancer chemotherapeutic regimens. The research delves into the intricate realm of RNA-dependent 5FU cytotoxicity, unraveling previously unclear cellular responses to its impact on RNA metabolism.   In more technical terms, we demonstrate that RQC functions as a guardian against translation stress caused by ribosome collisions during 5FU treatment. These findings reveal that acute 5FU exposure sets off a cascade of events, including the rapid induction of the mTOR signaling pathway, heightened mRNA translation initiation, and increased ribosome collisions, which activate the RQC mechanism. Crucially, our work underscores that a deficiency in RQC, specifically due to ZNF598 depletion, intensifies 5FU-induced cell death. Interestingly, this detrimental effect can be reversed by inhibiting mTOR or repressing mRNA translation initiation. Additionally, we unveil a previously unknown mTOR-dependent mechanism that enhances the RQC process, mitigating the cytotoxicity of 5FU and challenging its anticancer efficacy.   We extend our gratitude to all collaborators who contributed to this work! https://lnkd.in/ehKzRedc

Tumor-associated antigens (TAAs) and their derived peptides constitute an opportunity to design both personalized and off-the-shelf immunotherapies. In this study, researchers from Universitätsklinikum Erlangen present a data-driven computational pipeline that selects and ranks candidate antigens using a multi-pronged approach. Sanquin Diagnostic Services researchers Nadine van Kleef, Julian Freen-van Heeren, PhD Freen-van Heeren and Annelies Turksma contributed to this study with Sanquin's proprietary MHC exchange technology. With this technology, they validated binding of predicted MHC binding epitopes that was used to train the algorithm. Key highlights of the article: Expression Profile: The pipeline considers the expression profile of antigens in tumor biopsies and healthy tissues: minimizing the risk of immune-related adverse events is crucial. Network Analysis: An antigen indispensability index, derived from network analysis, further refines the selection process. This ensures that essential antigens are prioritized. Machine Learning Ensemble Model: Predictions based on peptide physicochemical characteristics and MHC binding capacity guide the selection. The model identifies immunogenicity, enhancing the chances of an effective immune response. Clinical Implications: By combining these approaches, the study identifies TAAs with the capacity to induce an anti-tumor immune response while minimizing tissue damage risk. If you are investigating novel (neo)antigen-specific immunotherapy, we are happy to help in validating binding to patient-specific HLA molecules in our MHC exchange assay. Of note, we can also use these exchanged MHC complexes to produce tetramers suitable for immunomonitoring of patient samples. Please contact us at info.pbs@sanquin.nl to learn more. #peptide #melanoma #immunotherapy #immunology #antigen https://lnkd.in/eSzyqQYK

🌟 𝐑𝐞𝐯𝐨𝐥𝐮𝐭𝐢𝐨𝐧𝐢𝐳𝐞 𝐂𝐚𝐧𝐜𝐞𝐫 𝐓𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐰𝐢𝐭𝐡 𝐀𝐆𝐓𝐂 𝐆𝐞𝐧𝐨𝐦𝐢𝐜𝐬' 𝐏𝐫𝐞𝐜𝐢𝐬𝐢𝐨𝐧 𝐌𝐞𝐝𝐢𝐜𝐢𝐧𝐞 𝐒𝐨𝐥𝐮𝐭𝐢𝐨𝐧𝐬 🌟 Healthcare professionals, oncologists, and cancer centers, are you ready to transform your approach to cancer care? At AGTC Genomics, we are committed to empowering you with cutting-edge molecular profiling and advanced genomic solutions to provide personalized treatment for your patients. 🔬 𝐏𝐞𝐫𝐬𝐨𝐧𝐚𝐥𝐢𝐳𝐞𝐝 𝐂𝐚𝐧𝐜𝐞𝐫 𝐂𝐚𝐫𝐞: Our molecular profiling services offer a deep understanding of cancer at the molecular level, enabling you to tailor treatment plans that are more effective and targeted. By analyzing DNA and RNA, we provide a comprehensive molecular blueprint of each tumor. 💡 𝐖𝐡𝐲 𝐂𝐡𝐨𝐨𝐬𝐞 𝐀𝐆𝐓𝐂 𝐆𝐞𝐧𝐨𝐦𝐢𝐜𝐬?: ✔ Best-in-Class Molecular Profiling: Combining our proprietary database and artificial intelligence with next-generation sequencing technology. ✔ Fast Turnaround Time: We prioritize delivering accurate results swiftly to ensure timely treatment decisions. ✔ Proven Technology: Our services are internationally validated and comply with global standards, ensuring reliability and high diagnostic power. ✔ Local Testing, High Data Security: Conducted in Malaysia with stringent data security standards. 🔍 𝐂𝐨𝐦𝐩𝐫𝐞𝐡𝐞𝐧𝐬𝐢𝐯𝐞 𝐒𝐨𝐥𝐮𝐭𝐢𝐨𝐧𝐬: ● CancerRiskDx™: Hereditary cancer screening for individuals with a family history of cancer. ● CancerScreenDx™: Early detection of over 85 types of cancer using a simple blood test. ● OncoDx™ and PreciseDx™: Comprehensive gene profiling for precise treatment decisions for patients with solid tumors or leukemia. ● LiquidDx™: Non-invasive liquid biopsy for metastatic cancer monitoring and treatment guidance. ● CancerTRACE™: Monitoring for cancer recurrence in survivors. 🌐 𝐉𝐨𝐢𝐧 𝐭𝐡𝐞 𝐅𝐮𝐭𝐮𝐫𝐞 𝐨𝐟 𝐂𝐚𝐧𝐜𝐞𝐫 𝐓𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭: Leverage our advanced genomic solutions to navigate among therapies, identify effective treatments, avoid unnecessary toxicities, and match patients to clinical trials. Let's work together to change the course of cancer treatment and improve patient outcomes. 🔗 Visit www.agtcgenomics.com to learn more about our services and how we can support you in delivering precision medicine. #Oncology #CancerTreatment #PrecisionMedicine #Genomics #HealthcareInnovation #CancerCare #AGTCGenomics #MedicalResearch #HealthcareProfessionals #CancerCenters