While immunotherapy has significantly improved outcomes for non-small cell lung cancer (NSCLC), many patients still don't benefit from current treatments. Dr. Oh has developed a CCL21-DC vaccine that uses engineered dendritic cells (DCs) to display tumor mutations and train the immune system while producing CCL21 protein to attract more tumor-killing T cells. He has completed a clinical trial combining this vaccine with pembrolizumab immunotherapy in patients with NSCLC, and collected tumor biopsies and blood samples before and after treatment. Using advanced sequencing techniques on these samples, he aims to understand how the vaccine affects tumor-targeting T cells and their interactions within tumors. These studies will guide future improvements in DC vaccines and other immunotherapies for lung cancer patients.
- Research Summary
The development of immunotherapy has significantly improved patient outcomes for non-small cell lung cancer (NSCLC). Unfortunately, many patients with NSCLC nevertheless do not benefit from current immunotherapies, and new strategies are required to move the field forward. Our lab has previously developed a cancer therapy called the CCL21-DC vaccine with the goal of overcoming immunotherapy resistance. This treatment involves the injection of dendritic cells (DCs), which are cells specialized in displaying tumor mutations and training the immune system to target those mutations. We have further engineered these DCs to produce CCL21, which is a protein that attracts more tumor-killing T cells. We recently performed a clinical trial studying the combination of the CCL21-DC vaccine and the immunotherapy drug pembrolizumab in patients with NSCLC. This study obtained tumor biopsies and blood samples from patients both before and after DC vaccine injections, and we plan to use these samples to better understand the impact of this therapy on the immune system.
We propose using cutting-edge sequencing techniques to assess whether the CCL21-DC vaccine leads to more tumor-targeting T cells both within the tumor and in the blood. We will also analyze the interactions between these T cells and other types of cells in the tumor. The results of our project will provide a more complete understanding of how DC vaccines impact the immune system and how tumors develop resistance. This project can therefore guide future efforts at improving DC vaccines and other immunotherapies for patients with lung cancer.
- Technical Abstract
The treatment of non-small cell lung cancer (NSCLC) has been transformed by the use of immune checkpoint inhibitors (ICIs), but many patients still do not respond to ICIs or subsequently develop resistance. The efficacy of ICIs is dependent on the recognition of tumor-specific neoantigens by T cells, a process that is supported by dendritic cells (DCs) that present antigens and activate T cells. Abetting the function of DCs thus represents a therapeutic avenue that can help overcome immunotherapy resistance. This goal can potentially be accomplished via direct injection of DCs as a cellular vaccine. DCs can further be engineered to express chemokines, such as CCL21, that promote T cell infiltration into the tumor. The Dubinett Laboratory has previously developed a CCL21-gene modified dendritic cell (CCL21-DC) vaccine, and we have conducted a phase I clinical trial studying the combination of the vaccine with the ICI pembrolizumab.
We plan to study the immunologic effects of the CCL21-DC vaccine using longitudinal patient biospecimens from this trial, including tumor biopsies and peripheral blood samples. The aims of this proposal are to 1) determine post-treatment changes in T cell clonal evolution and immune cell phenotypes; and 2) evaluate spatial relationships between T cells and the tumor microenvironment after treatment. Our objective is to characterize the impact of the CCL21-DC vaccine on antitumor T cell activity and identify cell-cell interactions that influence therapeutic efficacy. The results of these studies will inform future generations of DC vaccines and improve our understanding of immune resistance mechanisms in NSCLC.