Engineered Adoptive T-cell Therapy Prolongs Survival in a Preclinical Model of Advanced-Stage Ovarian Cancer

Adoptive T-cell therapy using high-affinity T-cell receptors (TCR) 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 liga...

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Vydáno v:	Cancer immunology research Ročník 7; číslo 9; s. 1412
Hlavní autoři:	Anderson, Kristin G, Voillet, Valentin, Bates, Breanna M, Chiu, Edison Y, Burnett, Madison G, Garcia, Nicolas M, Oda, Shannon K, Morse, Christopher B, Stromnes, Ingunn M, Drescher, Charles W, Gottardo, Raphael, Greenberg, Philip D
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.09.2019
Témata:	Animals Antigens, Neoplasm - genetics Antigens, Neoplasm - immunology CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell Line, Tumor Cytotoxicity, Immunologic Disease Models, Animal Female Gene Expression Gene Expression Profiling Genetic Engineering GPI-Linked Proteins - genetics GPI-Linked Proteins - immunology HLA-A Antigens - genetics HLA-A Antigens - immunology Humans Immunophenotyping Immunotherapy, Adoptive - adverse effects Immunotherapy, Adoptive - methods Mesothelin Mice Neoplasm Grading Neoplasm Staging Ovarian Neoplasms - genetics Ovarian Neoplasms - mortality Ovarian Neoplasms - pathology Ovarian Neoplasms - therapy Prognosis Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - metabolism Receptors, Chimeric Antigen - genetics Receptors, Chimeric Antigen - metabolism T-Lymphocytes - immunology T-Lymphocytes - metabolism Treatment Outcome Xenograft Model Antitumor Assays
ISSN:	2326-6074, 2326-6074
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Popis
Shrnutí:	Adoptive T-cell therapy using high-affinity T-cell receptors (TCR) 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 antitumor 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. We used deep transcriptome profiling and IHC analysis of human HGSOC tumors and disseminated mouse ID8 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 ID8 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. IHC and gene-expression profiling revealed striking similarities between tumors of both species, including processing/presentation of a leading candidate target antigen, suppressive immune cell infiltration, and expression of molecules that inhibit T-cell function. Engineered T cells targeting mesothelin infiltrated mouse tumors but became progressively dysfunctional and failed to persist. 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. Treatment with engineered T cells may have clinical applicability in patients with advanced-stage HGSOC.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2326-6074 2326-6074
DOI:	10.1158/2326-6066.CIR-19-0258