Blood 119 (15): 3440-3449 (2012-04-12)

Spranger S.; Jeremias I.; Wilde S.; Leisegang M.; Staerck L.; Mosetter B.; Uckert W.; Heemskerk M.H.M.; Schendel D.J.; Frankenberger B.

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

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.

Keywords: Animals, Xenograft Model Antitumor Assays, Transfection, Transgenic Mice, T-Cell Antigen Receptor Specificity, T-Cell Antigen Receptors, Neoplasms, Lymphocytes, K562 Cells, HEK293 Cells, Gene Therapy, Cell Growth Processes, Mice, Extracellular Matrix Proteins, Cultured Cells, CD44 Antigens, Adoptive Immunotherapy

Type: Article

PubMed: 22371883
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