Individualized mRNA vaccines evoke durable T cell immunity in adjuvant TNBC
U. Sahin, M. Schmidt, Evelyna Derhovanessian, A. Cortini, Isabel Vogler, Tana Omokoko, Eva Godehardt, Sebastian Attig, Sebastian Newrzela, J. Grützner, Nicole Bidmon, Stefanie Bolte, Sebastian Brachtendorf, T. Stuhlmann, D. Langer, D. Brüne, J. Blake, Anja Feldner, H. Lindman, A. Schneeweiss, MHR Eichbaum, Ö. Türeci
Abstract
. Here we assessed an individualized neoantigen mRNA vaccine in 14 patients with TNBC following surgery and after neoadjuvant or adjuvant therapy. In peripheral blood of nearly all patients, high-magnitude, vaccine-induced, mostly de novo T cell responses to multiple neoantigens were detected that remained functional for several years. Characterization of individual patients revealed that a large proportion of these T cells developed into two subsets: a late-differentiated phenotype with markers indicative of 'ready-to-act' cytotoxic effector T cells, and T cells with a stem cell-like memory phenotype. Eleven patients remained relapse-free for up to six years post-vaccination. Recurrence occurred in three patients: the individual with the weakest vaccine-induced T cell response relapsed, but achieved complete remission on subsequent anti-PD-1 therapy; another patient had a tumour with low major histocompatibility complex (MHC) class I expression with MHC class I-deficient cells growing out under vaccination; and the third patient was BRCA-positive and had a recurrence from a genetically distinct primary tumour. These findings demonstrate the feasibility of individualized RNA vaccines in TNBC, document persistence of vaccine-induced, functional neoantigen-specific T cells and provide insights into possible immune escape mechanisms that will guide future approaches.