It is becoming increasingly clear that somatic mutations in tumors induce nee-antigens and that these nee-antigens induce antitumoral immune response that may inhibit tumor growth. Malignancies with high mutation rates such as lung carcinoma have therefore statistically a higher chance of being under immunological attack than malignancies with few mutations. The clinical relevance of these immune responses seemed small as little antitumoral activity was noted Recently, treatment of advanced lung cancer patients with nivolumab, an inhibitor of a negative feedback loop on T cells (PD-1) revealed the dramatic "hidden" antitumoral immune response in some patients with objective tumor regression and long term survival. However, many of the treated patients enjoy little or no clinical benefit under PD-1 blockade, indicating that these patients did not raise an effective immune response against the mutanome

In this project, we aim to combine PD1-blockade with a dendritic cell (DC) vaccine to induce immunity to selected epitopes from the lung cancer's mutated genome. We anticipate that the combination of negative feedback blockade and active specific immune stimulation will result in higher response rates. In addition, we anticipate that pharmaceutical companies are unable, or not inclined, to perform cell-based and personalized clinical trials First, we will optimize the techniques to characterize the mutanome and transcriptome on tumor samples of patients by performing whole exome sequencing and RNAseq and the bioinformat1cs to process the data in a timely fashion.

Subsequently, cloning of tandem minigenes expressing these mutated residues and flanking amino acids and the in vitro transcription of synthetic mRNA will be optimized.After optimization, ten patients with newly diagnosed stage lllB/IV non-small cell lung carcinoma will be enrolled in a proof of concept intervention al clinical trial. While these patients receive 1st line standard systemic therapy, the expressed mutanome will be identified for each patient (as above) and synthetic mRNA encoding these possible neoant1gens will be produced. At disease relapse, patients will receive DC vaccins produced following our in house GMPcompliant protocol consisting of in vitro matured DC electroporated with the synthetic RNA encoding the nee-antigens in combination with nivolumab.Primary endpoints will be feasibility, safety/toxicity To assess possible efficacy, immunomonitoring to assess T cell responses against nee-antigens before and after vaccination will be a major aspect of the study. In this project, we bring together thoracic oncologists with expertise in DC therapy (Karim Vermaelen and team), expertise in T cell immunology and ATMP production (Bart Vandekerckhove) and cancer genomics (Kathleen Claes,Bjorn Menten)