Phase 1 trial of a CCL21 gene-modified dendritic cell vaccine plus pembrolizumab in advanced non-small cell lung cancer

Immune checkpoint inhibitors (ICIs) have transformed treatment for non-small cell lung cancer, but resistance to these therapies is common. A phase 1 trial at University of California Los Angeles evaluated the combination of intratumoral injection of a CCL2-expressing dendritic cell (CCL21-DC) vaccine and pembrolizumab in patients with advanced non-small cell lung cancer (aNSCLC). The primary objectives were to determine the maximum administered dose (MAD) in the dose escalation phase and the objective response rate (ORR) in the dose expansion phase. Eleven patients were enrolled in the dose escalation cohort, and 12 patients were treated in the dose expansion cohort at the MAD of 3 x 10⁷ cells per injection. The trial did not meet its primary endpoint for ORR as no objective responses were observed, though 36.8% of patients achieved a best response of stable disease. The combination therapy was well tolerated. Post-hoc analyses of longitudinal biopsies revealed that the therapy increased tumor infiltration by CD4+ T cells and novel T cell clones. Disease stability was associated with increased T cell receptor diversity and greater expansion of novel clones following therapy. However, many novel clones failed to persist over time, and immunosuppressive myeloid signaling signatures were identified across time points. The authors conclude that CCL21-DC vaccination combined with pembrolizumab can promote T cell infiltration; this did not translate into meaningful clinical efficacy, potentially due to limited tumor specificity of the T cell response and an inability to fully reprogram the tumor microenvironment.