Personalized neoantigen vaccine platform and longitudinal tracking of vaccine-related clonotypes enable the identification of tumor-specific TCRs

Abstract Effective immunotherapeutic strategies for high-grade serous ovarian cancer (HGSOC) remain limited despite evidence of tumor immunogenicity. Here, we report the longitudinal immune characterization of a patient with homologous recombination-deficient HGSOC treated with a personalized neoantigen-based dendritic cell (DC) vaccine during maintenance therapy with the PARP inhibitor olaparib. Following neoadjuvant chemotherapy and interval debulking surgery, the patient in complete response received an autologous monocyte-derived DC vaccine loaded with seven synthetic patient-specific neoantigen peptides (PEP-DC). The vaccine was well tolerated, with no serious vaccine-related adverse events. Comprehensive immune monitoring using flow cytometry, IFN- γ ELISpot assays, and bulk and single-cell T-cell receptor (TCR) sequencing revealed durable induction of neoantigen-specific immune responses, including polyfunctional T-cell responses and expansion of both de novo and pre-existing vaccine-related T-cell clonotypes. By integrating longitudinal TCR repertoire profiling with functional validation assays, we identified one vaccine-specific CD4 TCR and two CD8 TCRs recognizing tumor neoantigens. This proof-of-concept study demonstrates that personalized neoantigen vaccination can induce durable and diverse tumor-specific T-cell responses in ovarian cancer and establishes a framework for using vaccination as an in vivo platform to identify clinically relevant tumor-specific TCRs for future cellular therapies.