PuSH - Publication Server of Helmholtz Zentrum München: TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth <em>in vivo</em>.

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

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

Blood 119, 3440-3449 (2012)

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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.

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