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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Veröffentlicht in:Cancer immunology research Jg. 7; H. 9; S. 1412
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.09.2019
Schlagworte:
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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Zusammenfassung: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.
Bibliographie: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