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1.
N Engl J Med ; 386(22): 2112-2119, 2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35648703

RESUMO

A patient with progressive metastatic pancreatic cancer was treated with a single infusion of 16.2×109 autologous T cells that had been genetically engineered to clonally express two allogeneic HLA-C*08:02-restricted T-cell receptors (TCRs) targeting mutant KRAS G12D expressed by the tumors. The patient had regression of visceral metastases (overall partial response of 72% according to the Response Evaluation Criteria in Solid Tumors, version 1.1); the response was ongoing at 6 months. The engineered T cells constituted more than 2% of all the circulating peripheral-blood T cells 6 months after the cell transfer. In this patient, TCR gene therapy targeting the KRAS G12D driver mutation mediated the objective regression of metastatic pancreatic cancer. (Funded by the Providence Portland Medical Foundation.).


Assuntos
Terapia Genética , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Receptores de Antígenos de Linfócitos T , Genes Codificadores dos Receptores de Linfócitos T/genética , Terapia Genética/métodos , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/uso terapêutico , Neoplasias Pancreáticas
2.
Cancer Cell ; 40(4): 410-423.e7, 2022 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-35413272

RESUMO

Tumor-infiltrating neoantigen-reactive T cells can mediate regression of metastatic gastrointestinal cancers yet remain poorly characterized. We performed immunological screening against personalized neoantigens in combination with single-cell RNA sequencing on tumor-infiltrating lymphocytes from bile duct and pancreatic cancer patients to characterize the transcriptomic landscape of neoantigen-reactive T cells. We found that most neoantigen-reactive CD8+ T cells displayed an exhausted state with significant CXCL13 and GZMA co-expression compared with non-neoantigen-reactive bystander cells. Most neoantigen-reactive CD4+ T cells from a patient with bile duct cancer also exhibited an exhausted phenotype but with overexpression of HOPX or ADGRG1 while lacking IL7R expression. Thus, neoantigen-reactive T cells infiltrating gastrointestinal cancers harbor distinct transcriptomic signatures, which may provide new opportunities for harnessing these cells for therapy.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias Gastrointestinais , Antígenos de Neoplasias , Neoplasias Gastrointestinais/genética , Humanos , Linfócitos do Interstício Tumoral , Transcriptoma
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