Introduction: Treatment of severe COVID-19 disease can be challenging in immunocompromized patients due to newly emerging virus variants of concern (VOC) escaping the humoral response. Thus, T cells recognizing to date unmutated epitopes are not only relevant for patients' immune responses against VOC, but might also serve as a therapeutic option for patients with severe COVID-19 disease in the future, e.g. following allogenic stem cell transplantation. Methods: To this purpose, the activation, cytokine profile and specificity of T-cell clones against unmutated and omicron Spike (S)-protein was analyzed, HLA restriction was determined and most promising T-cell receptor (TCR) was introduced into allogeneic T cells via CRISPR/Cas9-mediated orthotopic TCR replacement. Finally, T-cell responses of engineered T cells was determined and durability of the TCR replacement measured. Perspective: SARS-CoV-2 specific engineered T cells recognizing a genomically stable region of the S-protein of all SARS-CoV 2 variants were successfully generated. Such transgenic T cells exhibit favorable effector functions and provide a treatment option of immunocompromised COVID-19 patients.Keywords: Orthotopic TCR replacement; SARS-CoV-2; T-cell engineering; T-cell therapy.

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