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Strong and sustained effector function of memory‐ versus naïve‐derived T cells upon T‐cell receptor RNA transfer: Implications for cellular therapy
Authors:Simone Thomas  Sebastian Klobuch  Katrin Besold  Bodo Plachter  Jan Dörrie  Niels Schaft  Matthias Theobald  Wolfgang Herr
Affiliation:1. Department of Medicine III, University Medical Center of Johannes Gutenberg‐University Mainz, , Mainz, Germany;2. Institute of Virology, University Medical Center of Johannes Gutenberg‐University Mainz, , Mainz, Germany;3. Department of Dermatology, Universit?tsklinikum Erlangen, , Erlangen, Germany
Abstract:
Current protocols used to select CMV‐specific T cells for adoptive immunotherapy focus on virus‐specific memory T cells from seropositive donors. However, this strategy is not feasible in patients undergoing allogeneic haematopoietic stem‐cell transplantation (HSCT) from CMV‐seronegative donors. Here, we redirected T cells of CMV‐seronegative donors with a human genetically engineered TCR recognizing an HLA‐A*0201‐binding peptide epitope of CMVpp65. To facilitate clinical translation of this approach, we used a non‐viral expression system based on in vitro transcribed RNA and electroporation. Although memory and naïve‐derived T‐cell subsets were both efficiently transfected by TCR‐RNA, memory‐derived T cells showed much stronger levels of HLA‐A*0201‐restricted cytolytic activity to CMV‐infected fibroblasts and maintained acquired function for 5–10 days. In addition to redirection of CD8+ cytotoxic T cells, TCR‐RNA transfection was capable of redirecting CD4+ T cells into potent Ag‐specific Th cells that efficiently triggered maturation of DCs. Our data suggest that memory rather than naïve‐derived T cells are the preferred subset for transient TCR expression by RNA electroporation, providing more efficient and sustained virus‐specific CD4+ and CD8+ T‐cell function. CMV TCR‐RNA may represent a suitable therapeutic ‘off‐the‐shelf’ reagent to be used in severe CMV infections of HSCT patients when endogenous CMV‐specific T‐cell immunity is insufficient.
Keywords:Cytomegalovirus  memory T cells  naive T cells  RNA  T‐cell receptor
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