title: TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo.
abstract: 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.
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Stefani
authors.initials: S
authors.lastname: Spranger
authors.forename: Irmela
authors.initials: I
authors.lastname: Jeremias
authors.forename: Susanne
authors.initials: S
authors.lastname: Wilde
authors.forename: Matthias
authors.initials: M
authors.lastname: Leisegang
authors.forename: Lilian
authors.initials: L
authors.lastname: Stärck
authors.forename: Barbara
authors.initials: B
authors.lastname: Mosetter
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Schendel
authors.forename: Bernhard
authors.initials: B
authors.lastname: Frankenberger
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods; D020014:K562 Cells; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D011948:Receptors, Antigen, T-Cell; C098946:hyaluronan-mediated motility receptor