Adoptive transfer of T cells transgenic for T cell receptors (TCR) is not yet clinically approved although TCR may harbor advantages compared to CAR. In particular, T cells can specifically recognize aberrant tumor cells in the context of neoantigen presentation at very low antigen levels. We have previously developed a mass spectrometry-based approach for neoantigen identification and characterized neoantigen-specific TCR harboring diverse qualities with respect to functionality and longevity of neoantigen-specific T cells. In this project, we aim to investigate these TCR exemplarily in the context of myeloma. TCR will be transferred into effector T cells by retroviral gene transfer and CRISPR-based orthotopic TCR replacement (OTR) and investigated with respect to functional analyses and transcriptional profiles after coincubation with myeloma cells in vitro and in vivo. T cells modified by neoantigen-specific TCR will be compared with myeloma-specific CAR focusing especially on the role of antigen sensing. Moreover, the impact of disease-specific therapeutics with known immune-modulatory effects will be investigated in combination with TCR- or CAR-transgenic T cells regarding functionality and transcriptional profiles aiming to optimize constructs and define optimal combinatorial strategies. In parallel, novel neoantigen-specific TCR with primary reactivity against myeloma-derived neoantigens will be isolated and investigated based on our well established neoantigen identification pipeline. Taken together, we will thereby provide novel strategies to target multiple myeloma by neoantigen-specific TCR-transgenic T cells and prospectively plan to deliver TCR-engineered T cells to patients with relapsed/refractory multiple myeloma.