Combination of a CCL21-gene modified dendritic cell vaccine and pembrolizumab induces immune responses in non-small cell lung cancer

Immune checkpoint inhibitors (ICIs) have transformed treatment for non-small cell lung cancer (NSCLC), but resistance to these therapies is common. We report results from a phase I trial combining intratumoral administration of a CCL21-gene modified dendritic cell (CCL21-DC) vaccine with pembrolizumab in patients with advanced NSCLC. Among 23 patients that received trial therapy, there were no dose-limiting toxicities and a low incidence of treatment-related adverse events. Although no objective responses were observed, 36.8% of patients had a best response of stable disease (SD). Correlative analyses of longitudinal tumor biopsies revealed that disease stability was associated with reduced tumor mutational heterogeneity and increased intratumoral T cell receptor diversity following therapy. Post-treatment tumor biopsies exhibited increased CD4+ T cell infiltration and the presence of novel T cell clones that predominantly possessed CD4+ memory T cell phenotypes. These novel clones experienced greater clonal expansion and a transition towards exhausted phenotypes in SD samples. However, many novel clones failed to persist over time, and immunosuppressive myeloid signaling signatures were identified especially in progressive disease samples. Our findings demonstrated that CCL21-DC vaccination combined with pembrolizumab is safe and can promote antitumor immune responses in a subset of patients. However, efficacy may have been constrained due to limited tumor specificity of the T cell response and an inability to fully reprogram the immunosuppressive tumor microenvironment.