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

Item Type:Article
Title:TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo
Creators Name:Spranger, S. and Jeremias, I. and Wilde, S. and Leisegang, M. and Staerck, L. and Mosetter, B. and Uckert, W. and Heemskerk, M.H.M. and Schendel, D.J. and Frankenberger, B.
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.
Keywords:Adoptive Immunotherapy, CD44 Antigens, Cell Growth Processes, Cultured Cells, Extracellular Matrix Proteins, Gene Therapy, HEK293 Cells, K562 Cells, Lymphocytes, Neoplasms, T-Cell Antigen Receptors, T-Cell Antigen Receptor Specificity, Transgenic Mice, Transfection, Xenograft Model Antitumor Assays, Animals, Mice
Source:Blood
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Volume:119
Number:15
Page Range:3440-3449
Date:12 April 2012
Official Publication:https://doi.org/10.1182/blood-2011-06-357939
PubMed:View item in PubMed

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