Details

Autor(en) / Beteiligte

• Spranger, Stefani
• Jeremias, Irmela
• Wilde, Susanne
• Leisegang, Matthias
• Stärck, Lilian
• Mosetter, Barbara
• Uckert, Wolfgang
• Heemskerk, Mirjam H.M.
• Schendel, Dolores J.
• Frankenberger, Bernhard

Titel

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

Ist Teil von

• Blood, 2012-04, Vol.119 (15), p.3440-3449

Ort / Verlag

Washington, DC: Elsevier Inc

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.