UCLA

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, despite recent advances in immune checkpoint inhibitor (ICI) therapy. ICIs have reshaped the therapeutic paradigm for NSCLC by offering durable clinical benefit in a subset of patients, but a substantial portion of patients fail to respond or develop tumor resistance. Immune escape mechanisms include impaired presentation of tumor antigens, limited T cell infiltration into the tumor, and immunosuppressive signals in the tumor microenvironment (TME). One potential strategy to overcome these factors involves improving the activity of antigen-presenting cells (APCs), such as dendritic cells (DCs), that are able to present tumor antigens and initiate tumor-specific T cell activation. DCs can be administered as an in situ vaccine to bolster APC functions in the TME, and they can be further engineered to express chemokines such as CCL21 in order to promote T cell trafficking into the tumor.

In this context, we completed a phase I clinical trial combining an autologous CCL21-gene modified dendritic cell (CCL21-DC) vaccine with pembrolizumab in patients with advanced stage NSCLC with the goal of overcoming resistance in ICI-refractory disease. There were no objective responses observed in this trial, but there was a 36.8% rate of disease control, including a case of disease stability lasting over 1 year as well as a case with post-vaccine resolution of an intracranial metastatic lesion. To better understand the immunologic impact of the trial therapy, we first performed a comprehensive characterization of the CCL21-DC vaccine product, which revealed significant cellular heterogeneity and variable CCL21 secretion. These findings suggested limitations to the DC vaccine manufacturing process that may adversely affect the consistency of therapeutic response. We next performed immune monitoring studies using longitudinal tumor biopsies and peripheral blood samples from patients on the clinical trial. We found that the CCL21-DC vaccine plus pembrolizumab reduced mutational intratumor heterogeneity (ITH) in patients who experienced disease control, indicative of active tumor immunoediting. The therapy also induced an increase in tumor infiltration by T cells and in particular early memory CD4+ T cells capable of migrating along a CCL21 gradient. Tumor samples with disease control exhibited greater T cell receptor (TCR) repertoire diversity and increased expansion of novel intratumoral clones. The immunologic changes within the tumor, however, were not consistently reflected in systemic immune signatures and were often transient in nature. Finally, in anticipation of further mechanistic studies of the CCL21-DC vaccine, we developed a murine NSCLC model consisting of clonal cell lines that can be used to modulate ITH and track clonal dynamics in response to immunotherapies.

Our findings overall suggest that the CCL21-DC vaccine can promote T cell infiltration and clonal diversification in the tumor, but there were limitations to the durability and depth of the resulting immunologic response. These results support further investigation of DC vaccine design and application as a strategy to enhance immunotherapy efficacy in NSCLC.