Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers

Haas, Andrew R.; Tanyi, János L.; O’Hara, Mark H.; Gladney, Whitney L.; Lacey, Simon F.; Torigian, Drew A.; Soulen, Michael C.; Tian, Lifeng; McGarvey, Maureen; Nelson, Anne Marie; Farabaugh, Caitlin S.; Moon, Edmund K.; Levine, Bruce L.; Melenhorst, J. Joseph; Plesa, Gabriela; June, Carl H.; Albelda, Steven Μ.; Beatty, Gregory L.

doi:10.1016/j.ymthe.2019.07.015

Cited by 233 publications

(177 citation statements)

References 47 publications

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“…When we surveyed the expression of known biomarkers, secretory clusters 2 and 3 exhibited the highest expression of PAX8, KRT7 and ESR1; and clusters 1 and 2 expressed relatively higher levels of OVGP1 and WFDC2 (which encodes ovarian cancer biomarker HE4) compared to cluster 3. FTSECs expressed high levels of less well known markers including cysteine rich secretory protein 3 (CRISP3) -a protein that has been implicated in epithelial cell proliferation and adhesion in the endometrium (Evans et al, 2015) but not in the fallopian tube; secretory leukocyte protease inhibitor (SLPI), expressed by HGSCs (Cancer Genome Atlas Research Network, 2011); mesothelin (MSLN), a proposed target for immunotherapy in ovarian cancer (Haas et al, 2019); and secreted chaperone clusterin (CLU) ( Figure 3B). Secretory cluster 1 was the most abundantly represented epithelial population in our data set, with, on average, 23.2土19.0% of the epithelial cells in each specimen assigned to this cluster (range 1.1-56.5%).…”

Section: Epithelial Components Of the Fallopian Tubementioning

confidence: 99%

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

Dinh

Lin

Abbasi

et al. 2020

Preprint

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The human fallopian tube harbors the cell-of-origin for the majority of high-grade serous 'ovarian' cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We performed single-cell transcriptomic profiling in 12 primary fallopian specimens from 8 patients, analyzing around 53,000 individual cells to map the major immune, fibroblastic and epithelial cell types present in this organ. We identified 10 epithelial sub-populations, characterized by diverse transcriptional programs including SOX17 (enriched in secretory epithelial cells), TTF3 and RFX3 (enriched in ciliated cells) and NR2F2 (enriched in early, partially differentiated secretory cells). Based on transcriptional signatures, we reconstructed a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3 high intermediate. Computational deconvolution of the cellular composition of advanced HGSCs based on epithelial subset signatures identified the 'early secretory' population as a likely precursor state for the majority of HGSCs. The signature of this rare population of cells comprised both epithelial (EPCAM, KRT) and mesenchymal (THY1, ACTA2) features, and was enriched in mesenchymal-type HGSCs (P = 6.7 x 10 -27 ), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

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Section: Epithelial Components Of the Fallopian Tubementioning

confidence: 99%

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

Dinh

Lin

Abbasi

et al. 2020

Preprint

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“…Both in vitro and in vivo experiments indicate that MSLN targeting CAR T cells are highly effective in controlling MSLN expressing tumors ( 63 ). The phase I trial NCT02159716 assessed the feasibility and safety of lentiviral CAR T-meso cells with or without lymphoreduction induced by cyclophosphamide pre-treatment, which enrolled in 15 patients (5 MPM, 5 serous OC, and 5 PDAC patients) ( 64 ). Results showed the MTD of CART-meso cells was 3 × 10 8 cells/m 2 without evidence for on-target toxicities, such as pleuritic, pericarditis, or peritonitis.…”

Section: Perspectives On Msln Role In Treatmentmentioning

confidence: 99%

Insights Into the Role of Mesothelin as a Diagnostic and Therapeutic Target in Ovarian Carcinoma

2020

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Ovarian malignancies remain the leading cause of death in female gynecological tumors. More than 70% of patients are diagnosed with advanced stage with extensive metastatic lesions in abdominal cavity due to lack of symptoms in early stage and sensitive diagnostic approaches. Mesothelin (MSLN), a glycosylphosphatidylinositol-anchored membrane glycoprotein, participates in cell adhesion, tumor progression, metastasis, and drug resistance. Despite this, the mechanism is still poorly understood. The differential expression pattern of MSLN in normal and cancer tissues makes it a promising target for diagnosis and therapeutic applications. Several clinical trials are underway to evaluate the safety and efficacy of MSLN-targeted drugs, including CAR T cells, immunotoxin, antibody-drug conjugates, and vaccine. This review is aimed to briefly discuss the characteristics of MSLN and the latest progress in MSLN targeting therapies.

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“…CAR T cells are producing remarkable results in hematological malignancies (Lim & June, 2017). Although the field is in its infancy, similar clinical responses with CAR T cell have not been observed thus far in solid tumors (Beatty et al, 2014;Beatty et al, 2018;Haas et al, 2019). In contrast to CARs, which contain CD3ζ and ITAM co-stimulatory signaling domains, TCRs instead rely on host cell machinery for downstream signaling.…”

Section: Of 36mentioning

confidence: 99%

T Cell Receptor Engineered Lymphocytes for Cancer Therapy

2020

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T lymphocytes are capable of specific recognition and elimination of target cells. Physiological antigen recognition is mediated by the T cell receptor (TCR), which is an alpha beta heterodimer comprising the products of randomly rearranged V, D, and J genes. The exquisite specificity and functionality of T cells can be leveraged for cancer therapy: specifically, the adoptive transfer of T cells that express tumor-reactive TCRs can induce regression of solid tumors in patients with advanced cancer. However, the isolation and expression of a tumor antigen-specific TCRs is a highly involved process that requires identifying an immunogenic epitope, ensuring human cells are of the correct haplotype, performing a laborious T cell expansion process, and carrying out downstream TCR sequencing and cloning. Recent advances in single-cell sequencing have begun to streamline this process. This protocol synthesizes and expands upon methodologies to generate, isolate, and engineer human T cells with tumor-reactive TCRs for adoptive cell therapy. Though this process is perhaps more arduous than the alternative strategy of using chimeric antigen receptors (CARs) for engineering, the ability to target intracellular proteins using TCRs substantially increases the types of antigens that can be safely targeted.

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Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers

Cited by 233 publications

References 47 publications

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

Insights Into the Role of Mesothelin as a Diagnostic and Therapeutic Target in Ovarian Carcinoma

T Cell Receptor Engineered Lymphocytes for Cancer Therapy

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