Immunotherapy has revolutionized cancer treatment and the management of autoimmune diseases
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Yang Chen
PROVIDER: PXD065308 | iProX | Mon Jun 23 00:00:00 BST 2025
REPOSITORIES: iProX
Similar Datasets
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:Adoptive cell therapy, a subset of cancer immunotherapy, is collection of therapeutic approaches which aim to redirect the immune system by reprogramming patient T-cells to target antigenic molecules differentially and specifically expressed in certain cancers. One promising immunotherapy technique is CAR T-cell therapy, where cancer cells are targeted through the expression a chimeric antigen receptor (CAR), a synthetic trans- membrane receptor that functionally compensates for the T-cell receptor (TCR) but targets a tumor associated antigen on the cancer cell surface. While CAR T-cell therapy is promising with two clinically approved second-generation CARs (Kymriah and Yescarta), few studies have investigated the mechanism of signal propagation in T-cells and no studies have investigated the potential signaling response in the target cells. To gain further insight to CAR-based signaling, we stimulated third generation CD19 CAR-expressing Jurkat T-cells by co-culture with SILAC labeled CD19HI Raji B-cells and used two phosphoenrichment strategies coupled with liquid chromatography-tandem mass spec- trometry (LC-MS/MS) to detect and analyze global phosphorylation changes in both cell populations. Analysis of the phosphopeptides originating from the CD19-CAR T cells revealed an increase in many phosphorylation events necessary for canonical TCR signaling. We also observed for the first time a significant decrease in B-cell receptor- related phosphopeptide abundance in CD19HI Raji B-cells after co-culture with CD19-targetted CAR T-cells.
2022-01-28 | PXD028109 | Pride
Project description:Adoptive cellular therapy has recently transformed the field of cancer immunotherapy, specifically the treatment of hematological malignancies, through the application of chimeric antigen receptor (CAR) T cells. While a tremendous step forward for cell therapy, current CAR T products face barriers to patient accessibility and clinical benefit. Their autologous nature renders the therapies patient selective and costly, and mechanisms of resistance to CAR T cells, including antigen downregulation/antigen-negative relapse, limit long-term therapeutic efficacy. In this letter, we report novel ex vivo HSC-derived mesothelin- CAR engineered NKT (AlloMCAR-iNKT) cell products that are pure, potent, and safe allogeneic cell therapies. AlloMCAR-iNKT cells execute ovarian cancer killing through a CAR-TCR-NK triple-mechanism, do not cause GvHD, and are resistant to allorejection. Our feeder- free, serum-free culture method promotes the speedy clinical translation of HSC engineered cells, and here we validate our system as a versatility platform for the development of designer “off-the-shelf” cellular products with high therapeutic potential to ovarian cancer patients.
2025-06-30 | GSE272764 | GEO
Project description:Salivary duct carcinoma is a rare and aggressive salivary gland cancer subtype with poor prognosis. Its mutational landscape has been described rather exhaustively but little is known regarding its functional genomics and tumor microenvironment. In this study, we combined transcriptomics and proteomics to obtain a first characterization of deregulated pathways, which revealed the importance of Notch, TGB-β, and interferon-γ signaling. We then associated computational biology, immunohistochemistry, multiplexed immunofluorescence, and digital imaging to start charting the cellular network within the microenvironment, identify two well-defined groups of tumors according to their immune infiltrate, find novel SDC immune checkpoints, and show the role macrophages and NK cells in immunosuppression. Furthermore, we showed a clear trend between recurrence free survival and M2 macrophage abundance, and, independently, α-SMA abundance – a measure of desmoplastic stromal reaction. Altogether, these many findings open new perspectives for SDC. Classical patient stratification according to the immune infiltrate should be applied before choosing an immunotherapy. The microenvironment offers new actionable targets such as macrophages or NK cells, or even fibroblasts or hyaluronic acid in the absence of immune infiltrate. Related therapies are developed e.g. against pancreatic tumors that could inspire equivalents for SDC. Combinations with drugs targeting SDC mutated genes might also contribute to patient-specific regimens.
2020-05-26 | PXD015885 | Pride
Project description:This ordinary differential equation model of the cellular kinetics and pharmacodynamics of CAR-T cell therapy is described in the publication:
Chaudhury, A., Zhu, X., Chu, L., Goliaei, A., June, C., Kearns, J. and Stein, A., 2020. Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic‐Pharmacodynamic Modeling Approaches. The Journal of Clinical Pharmacology, 60(S1).
DOI: 10.1002/jcph.1691
Comment:
This model is based on equations 4-5 from the manuscript.
Abstract:
Chimeric antigen receptor T cell (CAR-T cell) therapies have shown significant efficacy in CD19+ leukemias and lymphomas. There remain many challenges and questions for improving next-generation CAR-T cell therapies, and mathematical modeling of CAR-T cells may play a role in supporting further development. In this review, we introduce a mathematical modeling taxonomy for a set of relatively simple cellular kinetic-pharmacodynamic models that describe the in vivo dynamics of CAR-T cell and their interactions with cancer cells. We then discuss potential extensions of this model to include target binding, tumor distribution, cytokine-release syndrome, immunophenotype differentiation, and genotypic heterogeneity.
2024-09-02 | BIOMD0000001024 | BioModels
Project description:This ordinary differential equation model of the cellular kinetics and pharmacodynamics of CAR-T cell therapy is described in the publication:
Chaudhury, A., Zhu, X., Chu, L., Goliaei, A., June, C., Kearns, J. and Stein, A., 2020. Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic‐Pharmacodynamic Modeling Approaches. The Journal of Clinical Pharmacology, 60(S1).
DOI: 10.1002/jcph.1691
Comment:
This model is based on equations 7-9 from the manuscript.
Abstract:
Chimeric antigen receptor T cell (CAR-T cell) therapies have shown significant efficacy in CD19+ leukemias and lymphomas. There remain many challenges and questions for improving next-generation CAR-T cell therapies, and mathematical modeling of CAR-T cells may play a role in supporting further development. In this review, we introduce a mathematical modeling taxonomy for a set of relatively simple cellular kinetic-pharmacodynamic models that describe the in vivo dynamics of CAR-T cell and their interactions with cancer cells. We then discuss potential extensions of this model to include target binding, tumor distribution, cytokine-release syndrome, immunophenotype differentiation, and genotypic heterogeneity.
2024-09-02 | BIOMD0000001025 | BioModels
Project description:CD19-targeting chimeric antigen receptor (CAR) T cell have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, according to the recent clinical data, a significant portion of patients still do not benefit from the therapy, due various resistance mechanisms including the high expression of multiple inhibitory immune checkpoint receptors on activated CAR-T cells. Studies of checkpoint blockade immunotherapy using monoclonal antibodies have shown that simultaneously targeting inhibitory receptors that are functionally non-redundant can synergistically enhance anti-tumor responses. Here we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors can be downregulated simultaneously by a dual short-hairpin RNA (shRNA) cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations, PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4, and PD-1/TIGIT, and found that the CAR T with PD-1/TIGIT downregulation uniquely exhibited synergistic anti-tumor effect in mouse xenograft models compared to the single PD-1 downregulation and maintained cytolytic and proliferative capacity upon repeated antigen exposure. Importantly, functional and phenotypic analysis of CAR T cells as well as analysis of transcriptomic profiles suggests that downregulation of PD-1 enhances short-term effector function while downregulation of TIGIT is primarily responsible for maintaining a less-differentiated/exhausted state, providing a potential mechanism of the synergy. The PD-1/TIGIT downregulated CAR T cells generated from DLBCL patient-derived T cells following clinically applicable manufacturing process also showed a robust anti-tumor activity and significantly improved persistence in vivo compared to conventional CD19-targeting CAR T cells. Overall, our results demonstrate that the cell-intrinsic PD-1/TIGIT dual downregulation strategy may provide an effective way to overcome the immune checkpoint-mediated resistance in CAR T therapy.
2022-09-28 | GSE158676 | GEO
Project description:Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The cGAS-STING cytoplasmic double stranded DNA (dsDNA) sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils and NK populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, NK therapies or immune checkpoint blockade.
2022-06-28 | GSE206604 | GEO
Project description:Despite its proven efficacy for hematologic malignancies, chimeric antigen receptor (CAR) T cell therapy has met with limited success in treating solid tumors. While this represents a significant clinical challenge in cancer immunotherapy, preclinical efforts to assess and improve the efficacy and safety of CAR T therapy are hindered by our limited ability to model, probe, and modulate the complexity of cancer-immune interactions in solid tumors. Here, we present a microengineered platform for in vitro reproduction, real-time imaging, and in-depth analysis of malignant human solid tumors during CAR T therapy. Using a compartmentalized device with an externally accessible interface, this system makes it possible to engineer three-dimensional organotypic constructs composed of human tumor explants that can be vascularized and perfused with blood-borne immune cells in a controlled manner. We first present a microphysiological model of adenocarcinoma tumors in the human lung infused with CAR-T cells to demonstrate its capabilities to reproduce the three essential steps of targeting solid tumors, including CAR T cell recognition of tumor-associated antigens, infiltration, and survival and effector function in the tumor microenvironment. Using flow cytometry and single-cell RNA sequencing, we probe how the phenotype of CAR T cells changes during their recruitment and persistence. Furthermore, we use the sequencing data to discover a therapeutic target that can be pharmacologically inhibited in our model to significantly increase CAR T cell trafficking and their anti-tumor effects, for which we also present specific biomarkers identified by untargeted metabolomics analysis. This work provides a potentially powerful approach for mechanistic studies and preclinical screening of adoptive cell therapies for cancer and other complex diseases.
2025-06-25 | GSE240121 | GEO
Project description:Chimeric Antigen Receptor (CAR) T cell therapy has shown promise in treating hematologic malignancies. However, it is limited to individualized cell therapy and faces challenges, including high costs, extended preparation time, and limited efficacy against solid tumors. Here, we generated circular RNAs (circRNAs) encoding Chimeric Antigen Receptor (CAR) transmembrane proteins, referred to as circRNACAR, which mediated remarkable tumor killing in both T cells and macrophages. In addition, macrophages exhibited efficient phagocytosis of tumor cells and pro-inflammatory polarization induced by circRNACAR in vitro. We demonstrated that circRNACAR, delivered with immunocyte-tropic lipid nanoparticles (LNPs), significantly inhibited tumor growth, improved survival rates and induced a pro-inflammatory tumor microenvironment in mice. Importantly, the combination of circRNAAnti-HER2-CAR and circRNA-based cancer vaccines encoding the corresponding transmembrane HER2 antigen, termed circRNAHER2, exhibited synergistically enhanced anti-tumor activity. Notably, we found that circRNACAR could boost the level of circRNAHER2-elicited antibodies, which could mediate effective killing of HER2+ tumor cells by macrophages, indicating the potential of vaccination-elicited antibodies in developing novel immunotherapy. This proof-of-concept study demonstrated that the combination of circRNA-based in vivo CAR and vaccines, termed in vivo CAR-VAC, holds the potential to become an upgraded off-the-shelf immunotherapy, and also sheds light on the huge potential of vaccination-elicited antibodies in cancer immunotherapy.
2024-05-22 | GSE268105 | GEO