Recent next-generation sequencing (NGS) studies by our group documented the clonal architecture of the T cell repertoire in CLL, with T cell clones which persist and expand over time in treatment-naive CLL, appear disease-specific and may be shared among different patients, especially those belonging to stereotyped subsets, thereby indicating selection by restricted antigens that could actually be acting in a CLL subset-specific context. Furthermore, we have shown that BcR signaling inhibitors retain T cell clones that may have developed in response to tumor antigens; importantly, at least in the case of rituximab-idelalisib, these clones expand and may become activated, possibly contributing in the clinical response. Based on our extensive, albeit indirect, immunogenetic evidence regarding the existence of tumor-specific T cell clones that can potentially be recruited into antitumor responses, we here propose how to formally identify and fully characterize both immunogenic neoepitopes and the CD8 T cells that recognize them. We will take advantage of a novel, high-throughput method for detecting antigen-specific T cells using DNA-barcoded peptide-MHC-I multimers. Our study will focus on neoepitopes that may be conserved amongst CLL patients, with the ultimate goal to explore the possibility for a stratified treatment by means of engineered T cells or by peptide vaccines targeting such conserved epitopes.”
