TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo

• Published in: Blood 2012-04, Vol.119 (15), p.3440-3449
• Main Authors: Spranger, Stefani, Jeremias, Irmela, Wilde, Susanne, Leisegang, Matthias, Stärck, Lilian, Mosetter, Barbara, Uckert, Wolfgang, Heemskerk, Mirjam H.M., Schendel, Dolores J., Frankenberger, Bernhard
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Growth Processes - genetics; Cell Growth Processes - immunology; Cells, Cultured; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - immunology; Genetic Therapy - methods; HEK293 Cells; Hematologic and hematopoietic diseases; Humans; Hyaluronan Receptors - genetics; Hyaluronan Receptors - immunology; Immunotherapy, Adoptive - methods; K562 Cells; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphocytes - physiology; Medical sciences; Mice; Mice, Transgenic; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; T-Cell Antigen Receptor Specificity - genetics; Transfection; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-06-357939

The hyaluronan-mediated motility receptor (HMMR/Rhamm) is overexpressed in numerous tumor types, including acute lymphoid leukemia and acute myeloid leukemia (AML). Several studies have reported the existence of T-cell responses directed against HMMR in AML patients that are linked to better clinical outcome. Therefore, we explored the use of HMMR-specific TCRs for transgenic expression in lymphocytes and their in vivo impact on HMMR+ solid tumors and disseminated leukemia. We obtained TCRs via an in vitro priming approach in combination with CD137-mediated enrichment. Recipient lymphocytes expressing transgenic TCR revealed the specific tumor recognition pattern seen with the original T cells. Adoptive transfer experiments using a humanized xenograft mouse model resulted in significantly retarded solid tumor outgrowth, which was enhanced using IL-15–conditioned, TCR-transgenic effector memory cells. These cells also showed an increased potency to retard the outgrowth of disseminated AML, and this was further improved using CD8-enriched effector memory cells. To define a safe clinical setting for HMMR-TCR gene therapy, we analyzed transgenic T-cell recognition of hematopoietic stem cells (HSCs) and found on-target killing of HLA-A2+ HSCs. Our findings clearly limit the use of HMMR-TCR therapy to MHC- mismatched HSC transplantation, in which HLA-A2 differences can be used to restrict recognition to patient HSCs and leukemia.