title: Distinct transcriptional changes in non-small cell lung cancer patients associated with multi-antigenic RNActive® CV9201 immunotherapy.
abstract: We recently completed a phase I/IIa trial of RNActive® CV9201, a novel mRNA-based therapeutic vaccine targeting five tumor-associated antigens in non-small cell lung cancer (NSCLC) patients. The aim of the study presented here was to comprehensively analyze changes in peripheral blood during the vaccination period and to generate hypotheses facilitating the identification of potential biomarkers correlating with differential clinical outcomes post RNActive® immunotherapy. We performed whole-genome expression profiling in a subgroup of 22 stage IV NSCLC patients before and after initiation of treatment with CV9201. Utilizing an analytic approach based on blood transcriptional modules (BTMs), a previously described, sensitive tool for blood transcriptome data analysis, patients segregated into two major clusters based on transcriptional changes post RNActive® treatment. The first group of patients was characterized by the upregulation of an expression signature associated with myeloid cells and inflammation, whereas the other group exhibited an expression signature associated with T and NK cells. Patients with an enrichment of T and NK cell modules after treatment compared to baseline exhibited significantly longer progression-free and overall survival compared to patients with an upregulation of myeloid cell and inflammatory modules. Notably, these gene expression signatures were mutually exclusive and inversely correlated. Furthermore, our findings correlated with phenotypic data derived by flow cytometry as well as the neutrophil-to-lymphocyte ratio. Our study thus demonstrates non-overlapping, distinct transcriptional profiles correlating with survival warranting further validation for the development of biomarker candidates for mRNA-based immunotherapy.
authors.affiliation: CureVac AG , Tübingen, Germany.
authors.forename: Henoch S
authors.initials: HS
authors.lastname: Hong
authors.affiliation: CureVac AG , Tübingen, Germany.
authors.forename: Sven D
authors.initials: SD
authors.lastname: Koch
authors.affiliation: CureVac AG , Tübingen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Scheel
authors.affiliation: CureVac AG , Tübingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gnad-Vogt
authors.affiliation: CureVac AG , Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schröder
authors.affiliation: CureVac AG , Tübingen, Germany.
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Kallen
authors.affiliation: CureVac AG , Tübingen, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Wiegand
authors.affiliation: Center for Bioinformatics and Center for Bioinformatics, University of Tübingen , Germany.
authors.forename: Linus
authors.initials: L
authors.lastname: Backert
authors.affiliation: Center for Bioinformatics and Center for Bioinformatics, University of Tübingen, Germany; Quantitative Biology Center, University of Tübingen, Germany; Biomolecular Interactions, Max Planck Institute for Developmental Biology, Tübingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kohlbacher
authors.affiliation: CureVac AG , Tübingen, Germany.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Hoerr
authors.affiliation: CureVac AG , Tübingen, Germany.
authors.forename: Mariola
authors.initials: M
authors.lastname: Fotin-Mleczek
authors.affiliation: Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough , MA, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Billingsley
keywords: Biomarker candidates; NSCLC; cancer immunotherapy; mRNA-based vaccines; systems immunology; transcriptomics