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Co-STARs: Combining the advantages of chimeric antigen and T cell receptors for cancer targeting

ABSTRACT: Co-STARs: Combining the advantages of chimeric antigen and T cell receptors for cancer targeting

PROVIDER: PRJNA1107213 | ENA |

REPOSITORIES: ENA

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Co-STARs: Combining the advantages of chimeric antigen and T cell receptors for cancer targeting

Project description:Two types of engineered T cells have been successfully used to treat cancer patients, one with an antigen recognition domain derived from antibodies (chimeric antigen receptors, CARs) and the other derived from T-cell receptors (TCRs). CARs employ high-affinity antigen binding domains and co-stimulatory domains to augment T-cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here we describe a new type of receptor, called a Co-STAR (for Co-stimulatory Synthetic T-cell receptor and Antigen Receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments and co-stimulation is provided by two modules that drive NFκB signaling (MyD88 and CD40). We demonstrate that Co-STARs produce robust T-cell expansion and induce long-term regressions of mouse tumors bearing very low densities of antigen.

2025-07-09 | GSE266456 | GEO

Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion

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Chimeric EGFR ChIP-seq of an MCF-10A clone expressing chimeric EGFR and Erbb2 receptors

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Optimized delivery of dual co-stimulation and anti-tumor activity using parallel chimeric antigen receptors (pCARs)

Project description:Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T-cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity and specificity, pCAR T-cells consistently elicit superior anti-tumor activity both in vitro and in vivo, warranting clinical development.

2021-12-10 | GSE186557 | GEO

CARPOOL: A library-based platform to rapidly identify next generation chimeric antigen receptors

Project description:CARPOOL: A library-based platform to rapidly identify next generation chimeric antigen receptors

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Comparison of Transcriptional Profiles of T cells after Activation by TCR and Chimeric Antigen Receptors

Project description:Chimeric antigen receptor T (CAR-T) cell therapies for B cell malignancies demonstrate high response rate and durable disease control. However, in the case of solid tumors, CAR-T cells have shown dysfunction ascribed to some intrinsic defects in CAR signaling. Here, we construct a multi-chain chimeric receptor, termed as Synthetic T Cell Receptor and Antigen Receptor (STAR), which incorporates antigen-recognition domain of antibody and engages entire CD3 signaling machinery of T cell receptor (TCR). In multiple solid tumor models, STAR-T cells prominently outperform CAR-T cells without notable toxicity. STAR triggers strong and sensitive TCR-like signaling upon antigen stimulation. We compared the transcriptional profiles of STAR/CAR/TCR-T cells after stimulation for different time points (0, 6, 24, 72 hours), in order to figure out whether signaling difference of these receptors led to distinct gene expression. Our results showd that STAR activation phencopied TCR, while CAR drove a different program, displayed as various pathways related to effector function, cytokine response and cell survival were altered.

2021-02-14 | GSE160311 | GEO

Chimeric EGFR ChIP-seq of an MCF-10A clone expressing chimeric EGFR and Erbb2 receptors

Project description:Chimeric EGFR ChIP-seq of an MCF-10A clone expressing chimeric EGFR and Erbb2 receptors

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CSE1L and NUP37 proximity labeling in MCF10A cells expressing chimeric ErbB1:ErbB2 receptors

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RNA-seq profile of stimulated Tregs containing co-receptor signaling domain variant chimeric antigen receptors (CARs).

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