Innovative approaches to treating platinum-resistant ovarian cancer are gaining traction, particularly with the recent results from the PROTA trial, which investigated the combination of the oncolytic adenovirus TILT-123 and the immune checkpoint inhibitor pembrolizumab. This phase 1a trial, which included 15 women with refractory ovarian cancer, highlighted the potential of this treatment strategy to provide much-needed options for patients who have run out of effective therapies.
The study, conducted by researchers at TILT Biotherapeutics, focused on patients who had previously undergone multiple lines of systemic treatments, with many having either platinum-resistant or refractory cancer—a challenging scenario where traditional therapies often fail. With promising undertones from past research on oncolytic viruses and immunotherapy, the trial aimed to evaluate both the safety and efficacy of TILT-123, which has been genetically engineered to express tumor necrosis factor alpha (TNFα) and interleukin-2 (IL-2). These components stimulate the immune response and could theoretically boost the effectiveness of pembrolizumab, which aims to block the PD-1 pathway to rejuvenate T cells and improve anti-tumor activity.
Conducted between May 18, 2022, and November 7, 2023, this multicenter trial marked a significant collaboration effort to expand treatment avenues for women facing dire outcomes due to aggressive ovarian cancer. The findings reported disease control achieved by 64% of evaluable patients, signifying significant clinical responses even after extensive prior treatments. The treatment regimen resulted in median progression-free survival of 98 days and median overall survival of 190 days.
The administration of TILT-123 was well-tolerated among participants, with no dose-limiting toxicities observed, which is particularly noteworthy considering the harsh prognosis of the enrolled population. The most frequently reported adverse events included fever, fatigue, and nausea, affecting 40% of the patients. Crucially, the safety profile has encouraged the exploration of this combination therapy's broader application.
One standout finding was the correlation between initial serum anti-adenovirus neutralizing antibody titers and treatment efficacy, which indicates the immunological intricacies at play. Patients who exhibited higher antibody levels pre-treatment also showed significantly improved imaging responses post-therapy. This correlation raises important questions about the humoral immune response's role as both a potential biomarker for efficacy and as part of the mechanism of action of TILT-123.
While the results present an optimistic outlook, the trial also acknowledged the need for larger patient cohorts to draw conclusive efficacy analyses, particularly since the current sample size remains limited. Researchers already have plans underway to shift to phase 1b studies, which will combine TILT-123 and pembrolizumab with additional chemotherapy to build upon the findings of this trial.
The preliminary outcome holds promise for those with platinum-resistant ovarian cancer, providing evidence of the potential for oncolytic virotherapy combined with immunotherapy to evoke clinical responses and improve survival rates where traditional approaches have lagged. Further investigation will be necessary to refine this therapeutic strategy, but the results from this trial may illuminate new pathways to tackle this challenging disease effectively.