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

Abstract

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 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 immunohistochemical analysis of human HGSOC tumors and disseminated mouse ID8 VEGF tumors to compare immunologic features. We then evaluated the ability of CD8 T cells engineered to express a highaffinity TCR specific for mesothelin, an ovarian cancer antigen, to infiltrate advanced ID8 VEGF 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. Immunohistochemistry and gene expression profiling revealed striking similarities between tumors of both species, including processing/presentation of a leading candidate target antigen, suppressive immune cell

A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy

“…Solid tumors commonly exhibit an inhibitory TME that blocks T cell accumulation ( Anderson et al, 2017 ; D’Aloia et al, 2018 ). We previously developed a murine TCR targeting the mesothelin (Msln) antigen; TCR Msln T cells mediated antitumor efficacy but progressively up-regulated exhaustion markers and lost function in pancreatic ( Stromnes et al, 2015 ) and ovarian ( Anderson et al, 2019 ) tumor models. To determine if the Fas-4-1BB IFP could improve T cell persistence and antitumor activity, we generated a three-gene retroviral construct with the IFP and the β and α chains of TCR Msln ( Stromnes et al, 2015 ).…”

<p>Immunotherapy For Ovarian Cancer: Recent Advances And Combination Therapeutic Approaches</p>

“…[79][80][81][82] The main evidences from experimental animal models and clinical data on CAR-T and TCR-T role in OC are illustrated in Table 4. [83][84][85][86][87] Although their administration has shown a potential in the treatment of OC, it still has to face many challenges. Currently, several phase I/II clinical trials are ongoing.…”

An RGDKGE-Containing Cryptic Collagen Fragment Regulates Phosphorylation of Large Tumor Suppressor Kinase-1 and Controls Ovarian Tumor Growth by a Yes-Associated Protein–Dependent Mechanism

“…Murine ID8evascular endothelial growth factor (VEGF) ovarian carcinoma cells 22 were obtained from Dr. Philip Greenberg (University of Washington School of Medicine, Seattle, WA). ID8-VEGF cells were cultured in Dulbecco's modified Eagle's medium in the presence of 4% fetal bovine serum, 1.0% penicillin-streptomycin, 1.0% sodium pyruvate, and 1% of insulinetransferrinesodium selenite media supplements.…”