Neoadjuvant immune checkpoint therapy: Enabling insights into fundamental human immunology and clinical benefit

Abstract

While immune checkpoint therapy (ICT) has revolutionized cancer treatment, most patients with advanced disease fail to achieve durable benefit. To address this challenge, it is essential to integrate mechanistic research with clinical studies to: (1) understand response mechanisms, (2) identify patient-specific resistance pathways, (3) develop biomarkers for patient selection, and (4) design novel therapies to overcome resistance. We propose that incorporating "direct-in-patient" studies into clinical trials is crucial for bridging the gap between fundamental science and clinical oncology. In this review, we first highlight recent clinical success of ICT in the neoadjuvant setting, where treatment is given in earlier disease stages to improve outcomes. We then explore how neoadjuvant clinical trials could be utilized to drive mechanistic laboratory-based investigations. Finally, we discuss novel scientific concepts that will potentially aid in overcoming resistance to ICT, which will require future clinical trials to understand their impact on human immune responses.

Keywords: CTLA-4; PD-1; biomarkers; clinical trials; human immunology; immune checkpoint therapy; neoadjuvant.