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| Status |
Public on Aug 22, 2019 |
| Title |
Engineered adoptive T cell therapy prolongs survival in a preclinical model of advanced stage ovarian cancer [Mouse] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Purpose: Adoptive T cell therapy using high affinity T cell receptors (TCRs) to target tumor antigens has potential for improving outcomes in high-grade serous ovarian cancer (HGSOC) patients. Ovarian tumors develop a hostile, multicomponent tumor microenvironment containing suppressive cells, inhibitory ligands, and soluble factors that facilitate evasion of anti-tumor immune responses. Developing and validating an immunocompetent mouse model of metastatic ovarian cancer that shares antigenic and immunosuppressive qualities of human disease would facilitate establishing effective T cell therapies. Experimental Design: We used deep transcriptome profiling and immunohistochemical analysis of human HGSOC tumors and disseminated mouse ID8VEGF tumors to compare immunologic features. We then evaluated the ability of CD8 T cells engineered to express a high-affinity TCR specific for mesothelin, an ovarian cancer antigen, to infiltrate advanced stage ID8VEGF murine ovarian tumors and control tumor growth. Human CD8 T cells engineered to target mesothelin were also evaluated for ability to kill HLA-A2+ HGSOC lines. Results: Immunohistochemistry and gene expression profiling revealed striking similarities between tumors, including processing/presentation of similar candidate target antigens, suppressive immune cell infiltration, and expression of molecules that inhibit T cell function. Engineered T cells infiltrated mouse tumors but became progressively dysfunctional and failed to persist within tumors. Treatment with repeated doses of T cells maintained functional activity, significantly prolonging survival of mice harboring late-stage disease at treatment onset. Human CD8 T cells engineered to target mesothelin were tumoricidal for three HGSOC lines. Conclusions: Treatment with engineered T cells may have clinical applicability in patients with advanced-stage HGSOC.
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| Overall design |
Late-stage tumors isolated from 3 ID8-VEGF mice were analyzed.
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| Contributor(s) |
Anderson KG, Voillet V, Gottardo R, Greenberg PD |
| Citation(s) |
31337659 |
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| Submission date |
Sep 20, 2018 |
| Last update date |
Aug 22, 2019 |
| Contact name |
Kristin Gail Anderson |
| Organization name |
Fred Hutchinson Cancer Research Center
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| Department |
Clinical Research Division
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| Lab |
Philip Greenberg Lab
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| Street address |
1100 Fairview Ave N
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| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98109 |
| Country |
USA |
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| Platforms (1) |
| GPL20775 |
[MTA-1_0] Affymetrix Mouse Transcriptome Array 1.0 [transcript (gene) CSV version] |
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| Samples (3) |
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| This SubSeries is part of SuperSeries: |
| GSE120264 |
Engineered adoptive T cell therapy prolongs survival in a preclinical model of advanced stage ovarian cancer |
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| Relations |
| BioProject |
PRJNA492329 |
