Submitted March 6, 2009
Accepted July 2, 2009
Dendritic cells pulsed with RNA encoding allogeneic MHC and antigen induce T cells with superior anti-tumor activity and higher TCR functional avidity
Susanne Wilde, Daniel Sommermeyer, Bernhard Frankenberger, Matthias Schiemann, Slavoljub Milosevic, Stefani Spranger, Heike Pohla, Wolfgang Uckert, Dirk H. Busch, and Dolores J. Schendel*
Institute of Molecular Immunology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Munich, Germany
Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
Institute of Medical Microbiology, Immunology, and Hygiene, Technical University Munich, Munich, Germany
Laboratory of Tumor Immunology, LIFE-Center, Ludwig-Maximilians-University, Munich, Germany
Humboldt University Berlin, Institute of Biology, Berlin, Germany
Clinical Cooperation Group 'Antigen-Specific Immunotherapy', Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Munich, Germany
Clinical Cooperation Group 'Immune Monitoring', Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Munich, Germany
* Corresponding author; email: schendel{at}helmholtz-muenchen.de.
Adoptive transfer of T cells expressing transgenic T cell receptors (TCR) with anti-tumor function is a hopeful new therapy for patients with advanced tumors however there is a critical bottleneck in identifying high-affinity TCR specificities needed to treat different malignancies. We have developed a strategy using autologous dendritic cells co-transfected with RNA encoding an allogeneic MHC molecule and a tumor-associated antigen (TAA) to obtain allo-restricted peptide-specific T cells having superior capacity to recognize tumor cells and higher functional avidity. This approach provides maximum flexibility since any MHC molecule and any TAA can be combined in the dendritic cells used for priming of autologous T cells. TCR of allo-restricted T cells when expressed as transgenes in activated peripheral blood lymphocytes transferred superior function compared with self-restricted TCR. This approach allows high-avidity T cells and TCR specific for tumor-associated self-peptides to be easily obtained for direct adoptive T cell therapy or for isolation of therapeutic transgenic TCR sequences.
