Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1024050 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26283670_1.fastq.gz | Fastqsanger.gz | |||
| SRR26283670_2.fastq.gz | Fastqsanger.gz | |||
| SRR26283671_1.fastq.gz | Fastqsanger.gz | |||
| SRR26283671_2.fastq.gz | Fastqsanger.gz | |||
| SRR26283672_1.fastq.gz | Fastqsanger.gz |
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Project description:Probiotic neoantigen delivery vectors for precision cancer immunotherapy
| PRJNA1024935 | ENA
Project description:Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo. With emerging evidence that bacteria naturally home to tumors and modulate anti-tumor immunity one promising application is the development of bacterial vectors as precision cancer vaccines. In this study, we engineered probiotic E. coli Nissle 1917 (EcN) as an anti-tumor vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system which drives potent and specific T cell–mediated anti‑cancer immunity that effectively controls or eliminates tumor growth and extends survival in advanced murine primary and metastatic solid tumors. We demonstrate that the elicited anti-tumor immune response involves extensive priming and activation of neoantigen-specific CD4+ and CD8+ T cells, broader activation of both T and NK cells, and a reduction of tumor-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumor‑specific neoantigen–derived epitopes within the optimal context to induce specific, effective, and durable systemic anti-tumor immunity.
2024-07-21 | GSE244808 | GEO
Project description:Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.
2023-12-01 | GSE248401 | GEO
Project description:Targeting tumor-specific neoantigens is promising for cancer immunotherapy, yet their ultra-low expression on tumor cells poses significant challenges for T cell therapies. Here, we found that chimeric antigen receptors (CARs) exhibited 10-100 times lower sensitivity compared to T cell receptors (TCRs) when targeting p53R175H common neoantigen. To enhance CAR functionality, we introduce T cell receptor fusion construct (TRuC) and synthetic TCR and antigen receptor (STAR). Our data demonstrate that STAR, which incorporates TCR-mimic antibody fragments and complete TCR signaling machinery, optimally reproduces antigen sensitivity of TCRs. STAR outperforms both CAR and TRuC in redirecting both CD8+ and CD4+ T cells to recognize HLA class I neoantigens. In vitro, human primary T cells engineered with STAR kill multiple cancer cell lines with low neoantigen density better than CAR-T and TRuC-T cells. In tumor mouse models, STAR-T cells outperform CAR-T and TRuC-T cells in controlling neoantigen-low breast cancer and leukemia. Taken together, our findings highlight severe defects in CAR sensitivity and introduce STAR as a more sensitive synthetic receptor, providing a new framework for T cell-based immunotherapy targeting tumors with low neoantigen density.
2024-10-31 | GSE279137 | GEO
Project description:Immunotherapy has transformed cancer treatment. However, current immunotherapy modalities face many limitations. Here, we developed a new form of immunotherapy that elicits anti-tumor immunity through multiplexed activation of endogenous genes. We leveraged the CRISPR activation (CRISPRa) system to directly augment the in situ expression of endogenous genes, and thereby the presentation of tumor antigens, leading to dramatic anti-tumor immune responses. Deploying this as a cell-based vaccination strategy showed efficacy in both prophylactic and therapeutic settings. Intratumoral adeno-associated virus delivery of CRISPRa libraries elicited strong anti-tumor immunity across multiple cancer types. Precision targeting of mutated gene sets eradicated a large fraction of established tumors at both local and distant sites. This treatment modality led to alterations of the tumor microenvironment, marked by enhanced T cell infiltration and anti-tumor immune signatures. Multiplexed endogenous gene activation may serve as a versatile and highly scalable strategy to elicit potent immune responses against cancer.
2020-04-14 | GSE133983 | GEO
Project description:Neoantigens derived from non-synonymous somatic mutations, especially gene fusion mutation, are restricted to tumor cells and thus considered ideal targets for T-cell receptor-engineering T-cells (TCR-T) immunotherapy. Adoptive transfer of neoantigen-specific TCR-T cells preferentially exhibit potent cytotoxicity preferentially to tumor cells, and has shown promising efficacy in several preclinical human cancer models. However, most neoantigens are unique to individual patient, which hinders the application of TCR-T cell therapy. In this study, we first discovered a paired / TCR repertoire, Tcr-1, that specifically targeted STY-SSX fusion neoantigen shared by almost all synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) exhibited antigen-specific HLA-A*2402-restricted antitumoral activity against synovial sarcomas cell both in vitro and in vivo. Furthermore, to furtherly extend its application beyond synovial sarcomas, we innovatively developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into enzyme-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (FNeo-AgNPs) for tumor targeting delivery. As expected, FNeo-AgNPs were proven of great tumor penetration, and local release. In situ modification was able to direct engineered Tcr-T1 against to other malignant gastric cancer cell line with significant antigen-specific HLA-A*2402-restricted cytotoxicity resulting in remarkable tumor regression and prolonging survival in both subcutaneous and peritoneally disseminated preclinical models, despite of their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has a great potential for further clinical investigation, and provide a now insight for future TCR-T cell therapy development.
2024-11-18 | GSE243535 | GEO
Project description:Overcoming barriers to the generation of antitumor immunity to self-and neo-antigens is a central concern of cancer immunotherapy. This study investigated the effect of interactions between ovarian cancer (OC) cells and the tumor microenvironment (TME) on the ability of oncolytic virotherapy to activate responsiveness of self antigen-specific and neoantigen-specific CD8+ T lymphocytes in tolerogenic and wild-type (WT) murine tumor models, respectively
2022-06-30 | GSE199880 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is highly intratumorally heterogeneous and has several subtypes. Effective gene delivery to all PDAC cells is essential for modulating gene expression and identifying potential gene-based therapeutic targets in PDAC. Most current gene delivery systems for pancreatic cells are optimized for islet or acinar cells. Lentiviral vectors are the current main gene delivery vectors for PDAC, but their transduction efficiencies vary depending on pancreatic cell type, and are especially poor for the classical subtype of PDAC cells from both primary tumors and cell lines. Herein, we systemically compare transduction efficiencies of glycoprotein G of vesicular stomatitis virus (VSV-G)-pseudotyped lentiviral and Sendai viral vectors in human normal pancreatic ductal and PDAC cells. We find that the Sendai viral vector gives the most robust gene delivery efficiency regardless of PDAC cell type. Therefore, we propose using Sendai viral vectors for transducing ectopic genes into PDAC cells.
2024-04-08 | GSE247243 | GEO