Rebecca L. Porter

CAR memory–like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory–like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.

Checkpoint Blockade: Not Yet NINJA Status in Ovarian Cancer

Botensilimab (Fc-enhanced anti–CTLA-4 antibody) plus balstilimab (anti–PD-1 antibody) in patients with treatment-refractory ovarian cancer

Background Patients with platinum-resistant/refractory ovarian cancer (PROC) experience suboptimal outcomes, highlighting an immediate need for novel therapies. This phase 1b study investigated the safety and efficacy of botensilimab (BOT), a fragment crystallizable (Fc)-enhanced anti–cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody with differentiated mechanisms of action from first-generation CTLA-4 inhibitors, plus balstilimab (BAL; anti–programmed cell death protein 1 antibody), in an expanded cohort of patients with treatment-refractory ovarian cancer. Methods BOT was administered intravenously at 1 mg/kg or 2 mg/kg every 6 weeks in combination with BAL intravenously at 3 mg/kg every 2 weeks (up to 2 years). The primary objectives were to assess safety and tolerability. Efficacy end points included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. Overall survival (OS) was an exploratory end point. Results Overall, 44 patients were evaluable for safety (with a median of 3 prior lines of therapy; median follow-up 9.6 months (range, 0.6‐36.6)), and 35 for efficacy. The most common treatment-related adverse event was diarrhea/colitis (43%; 16% grade 3) with no treatment-related deaths. RECIST-confirmed ORR was 23% (8/35; 95% CI 10% to 40%; one complete (CR), seven partial responses (PRs)) and clinical benefit rate (CR, PR, or stable disease ≥24 weeks) was 31% (11/35; 95% CI 17% to 49%). Median DOR was 9.7 months (95% CI 2.8 to not reached (NR)), median PFS was 2.8 months (95% CI 1.4 to 5.5), median OS was 14.8 months (95% CI 12.1 to NR), and 12-month OS was 75% (95% CI 55% to 86%). Immune phenotypic analyses and biomarker data revealed significantly higher FcγRIIIA+CD11c+ cells and higher programmed death-ligand 1 expression in responding patients, a strong association between T-cell infiltrated tumors and clinical benefit, and differences in immune architecture across histologic subtypes. Conclusion The BOT/BAL combination demonstrated deep, durable responses and complete remissions in patients with treatment-refractory ovarian cancer where no standard treatments are currently available. RECIST under-represented clinical benefit with 11 patients achieving prolonged/clinically meaningful stable disease (or better) for ≥24 weeks. Toxicities were manageable and reversible. The encouraging clinical activity of BOT/BAL in heavily pretreated patients, as well as biomarker associations, warrants further investigation of this combination.