Enhancing CAR T Cell Therapy in Patients with Pancreatic Cancer
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ABSTRACT:
PROVIDER: PRJNA1154619 | ENA |
REPOSITORIES: ENA
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Project description:Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival time of less than a year, highlighting the urgent need for treatment advancements. We conducted a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with unresectable or metastatic PDAC. Though therapy was well tolerated, limited clinical efficacy was observed. Analyses of patient samples provide insights into mechanisms of treatment resistance. Using single-cell genomic approaches, we found that CAR T cells post-infusion express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for Treg and GZMK+ phenotypes. Single knockout of ID3 or SOX4 appeared to enhance efficacy in xenograft models, but eventually failed, whereas double-knockout ID3 and SOX4 CAR T cells exhibit prolonged relapse-free survival, demonstrating sustained therapeutic effect and a potential avenue for engineering a more potent CAR T cell in pancreatic cancer.
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Project description:Neuroblastoma is a common pediatric extracranial solid tumor, that arises in the developing sympathetic nervous system. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated promising clinical responses, yet its effectiveness in neuroblastoma benefits only a subset of patients. We evaluated the immunosuppressive secretome of neuroblastoma tumoroids that attenuate CAR T-cells function and efficacy. Secreted proteins were collected from tumoroids and identified by shotgun MS.
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Project description:A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive tumor microenvironment (TME), which is densely populated and supported by protumoral glioma-associated microglia and macrophages (GAMs). Targeting CD47, a don't-eat-me signal overexpressed by tumor cells, disrupts the CD47-SIRPalpha axis and induces GAM phagocytic function. However, antibody-mediated CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. To overcome these limitations, we combined local CAR T cell therapy with paracrine GAM modulation to effectively eliminate GBM. To this end, we engineered a new CAR T cell against epidermal growth factor receptor variant III (EGFRvIII) that constitutively secretes a signal regulatory protein gamma (SIRPgamma)-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eliminated EGFRvIII+ GBM in a dose-dependent manner in vitro and eradicated orthotopically xenografted EGFRvIII-mosaic GBM by locoregional application in vivo. This resulted in significant tumor-free long-term survival, followed by partial tumor control upon tumor re-challenge. Combining anti-CD47 antibodies with anti-EGFRvIII CAR T cells failed to achieve a similar therapeutic effect, underscoring the importance of sustained paracrine GAM modulation. Multidimensional brain immunofluorescence microscopy and in-depth spectral flow cytometry on GBM-xenografted brains showed that anti-EGFRvIII-SGRP CAR T cells accelerated GBM clearance, increased CD68+ cell trafficking to tumor scar sites and promoted GAM-mediated tumor cell uptake. In a peripheral lymphoma mouse xenograft model, anti-CD19-SGRP CAR T cells had superior efficacy to conventional anti-CD19 CAR T cells. Validation on human GBM explants revealed that anti-EGFRvIII-SGRP CAR T cells had a similar tumor-killing capacity to anti-EGFRvIII CAR monotherapy but showed a slight improvement in the maintenance of tumor-infiltrated CD14+ cells. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate immune TME. This results in the additive elimination of bystander EGFRvIII- tumor cells in a manner that overcomes the main mechanisms of CAR T cell therapy resistance, including tumor innate immune suppression and antigen escape.
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Project description:The study aimed to assess plasma proteomic and metabolomic profiling in patients with B-ALL during humanized anti-CD19-CAR-T cell therapy
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Project description:The study aimed to assess plasma proteomic and metabolomic profiling in patients with B-ALL during humanized anti-CD19-CAR-T cell therapy
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Project description:<p>Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (r/r) large B-cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether a MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme which regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers which resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine and lysophospholipids which was validated in an independent set from another institution as predictive of non-durable response to CAR T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL. </p>
2022-10-31 | MTBLS5381 | MetaboLights
Project description:Although most patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) receiving CD19-targeted chimeric antigen receptor (CAR) T cell therapy achieve remission, loss of CAR T cell functionality and subsequent relapse remains an unmet therapeutic need. We applied an integrative approach to study the immunometabolism of pre- and post-infusion CD19-CAR T cells of patients with relapsed/refractory B-ALL. Pre-infusion CAR T cells of long-term responders (LTR) had increased oxidative phosphorylation, fatty acid oxidation, and pentose phosphate pathway activities, higher mitochondrial mass, tighter cristae, and lower mTOR expression compared to products of short-term responders. Post-infusion CAR T cells in bone marrow (BM) of LTR had high immunometabolic plasticity and mTOR-pS6 expression supported by the BM microenvironment. Transient inhibition of mTOR during manufacture induced metabolic reprogramming and enhanced anti-tumor activity of CAR T cells. Our findings provide insight into immunometabolic determinants of long-term response and suggest a therapeutic strategy to improve long-term remission.
2025-06-05 | GSE298663 | GEO
Project description:We employed single-cell RNA sequencing combined with BCR/TCR profiling to study PBMCs from 5 SLE patients before treatment and after peripheral B-cell reconstitution following dual-target (BCMA/CD19) CAR-T therapy. PBMCs were analyzed to characterize dynamic immune cell subsets, BCR/TCR clonal expansion, and SLE-related pathways. This study provides a single-cell landscape of dual-target CAR-T therapy in SLE, offering insights into efficacy and potential biomarkers.
2025-08-08 | GSE304878 | GEO
Project description:Clinical responses to CD19-directed CAR T cell therapy in B cell malignancies are strongly associated with robust CAR T cell expansion in the peripheral blood. In contrast, CAR T cells targeting solid tumors do not encounter cognate antigen in the periphery, resulting in limited expansion and subtherapeutic peak concentrations. To overcome this, we engineered dual-targeted and dual-co-stimulated CAR T cells (CD19/28ζ-M5BBζ) that recognize CD19+ B cells, thereby promoting peripheral expansion and increasing the pool of solid tumor-directed CAR T cells available for tumor infiltration without the need for lymphodepletion. In immunocompetent C57BL/6 mouse models of pancreatic ductal adenocarcinoma and melanoma, these dual-targeted CAR T cells demonstrated enhanced peripheral expansion, improved anti-tumor efficacy, and increased survival without added dysfunction or toxicity compared to single antigen-targeted CAR T cells. We translated our findings to human CAR T cells by developing a novel pancreatic/xenograft model with CD19⁺ B cells in the periphery and again demonstrated that treatment with dual CAR T cells showed significantly enhanced tumor clearance and survival compared to single antigen-targeted CAR T cells. In conclusion, we demonstrate that dual-targeted CAR T cells boost peripheral expansion, and anti-tumor efficacy, providing a strategy for enhancing outcomes for patients treated with clinical CAR T products targeting solid tumors.
2025-09-19 | GSE307863 | GEO
Project description:Immunotherapy using CD19-directed chimeric antigen receptor (CAR)-T cells has shown excellent results for treatment of B-cell leukaemia and lymphoma. To produce CAR-T cells, the patient’s own T cells are isolated from the blood and modified in a laboratory with a genetic vector to express a tumor antigen-directed CAR on its surface. The CAR-T cells are then expanded in numbers and given back to the patient with the aim to eradicate the tumors. However, some patients display primary resistance to CAR-T treatment while others relapse quickly after CAR-T treatment. In this experiment, we seek to understand whether the quality of the individual CAR-T cell product the patients were given can predict outcome to the therapy. We investigate the transcriptional profile of the individual CAR-T infusion products using single-cell RNA sequencing. In this dataset, we identified a T cell subset correlating with response that could be used as an indicator for clinical outcome. Targeted RNA and protein single-cell libraries were obtained using the BD Rhapsody platform (BD Biosciences). In total four separate targeted libraries were produced with 6 patients per library. Sequencing was performed on NovaSeq 6000 S1 sequencer at the SNP&SEQ Technology Platform (Uppsala, Sweden). The raw scRNA-seq data was pre-processed by BD Biosciences using the Rhapsody Analysis pipeline to convert the raw reads into Unique Molecular Identifier (UMI) counts. UMIs are further adjusted within Rhapsody by applying BD’s Recursive Substitution Error Correction (RSEC) and Distribution-Based Error Correction (DBEC) in order to remove false UMIs caused by sequencing or library preparation errors. Pooled samples were deconvoluted using Sample-tag reads. The scRNA-seq and AbSeq counts were loaded, processed and used for clustering and differential gene expression with Seurat v. 4.0.0.
2023-07-24 | E-MTAB-12407 | biostudies-arrayexpress