Mirvetuximab Soravtansine Induces Potent Cytotoxicity and Bystander Effect in Cisplatin-Resistant Germ Cell Tumor Cells

Patients with treatment-refractory/relapsing germ cell tumors (GCTs) have a dismal prognosis due to a lack of any effective therapy. Moreover, the efficacy of newly approved targeted therapies remains unexplored for cisplatin-resistant GCTs. Previously, it was demonstrated that folate receptor α (FRα) is overexpressed in many tumor types and efficiently targeted by the antibody-drug conjugate (ADC) mirvetuximab soravtansine (MIRV) in cisplatin-resistant cancers. We hypothesized that FRα represents an attractive target for treating treatment-refractory GCTs. We determined the expression of the <i>FOLR1</i> gene in a broad range of GCT cell lines and tumor xenografts. We tested the antitumor efficacy of MIRV on cisplatin-resistant GCT cells in vitro and explored the ability of MIRV treatment to induce a bystander effect in the direct coculture of FRα-high and FRα-low cells. We found that the <i>FOLR1</i> gene has significantly higher expression in testicular GCTs (TGCTs) than in normal testicular tissue. <i>FOLR1</i> is highly expressed in the TCam2, JEG3, JAR, and NOY1 cell lines and their respective cisplatin-resistant variants. MIRV treatment induced apoptosis and a potent antiproliferative effect in cisplatin-resistant GCT cells in adherent and 3D spheroid cultures in vitro. A significant decrease in FRα-low 2102EP_R_NL cells was observed in the presence of FRα-high NOY1_R_SK in the presence of 12.5 nM MIRV, showing a potent bystander effect in the direct coculture. Immunohistochemical analysis confirmed significantly higher Folr1 protein expression in patients with TGCTs postchemotherapy than in chemo-naïve patients, as well as in patients with an unfavorable prognosis. In this study, we present data suggesting that the <i>FOLR1</i> gene is highly expressed in (T)GCT cells in vitro and in vivo, and anti-FRα-targeting therapies should be investigated as a treatment modality in a subset of patients with TGCTs. Moreover, MIRV induced significant antitumor and bystander effects, thus showing its potential in further preclinical exploration and drug repurposing for a salvage treatment regime in refractory (T)GCT disease.