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: Stefani Spranger, Irmela Jeremias, Susanne Wilde, Matthias Leisegang, Lilian Stärck, Barbara Mosetter, Wolfgang Uckert, Mirjam H M Heemskerk, Dolores J Schendel, Bernhard Frankenberger
• Journal: Blood (Blood) Vol. 119 Issue 15 Pg. 3440-9 (Apr 12 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22371883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Extracellular Matrix Proteins
• Hyaluronan Receptors
• Receptors, Antigen, T-Cell
• hyaluronan-mediated motility receptor

Topics

• Animals
• Cell Growth Processes (genetics, immunology)
• Cells, Cultured
• Extracellular Matrix Proteins (genetics, immunology)
• Genetic Therapy (methods)
• HEK293 Cells
• Humans
• Hyaluronan Receptors (genetics, immunology)
• Immunotherapy, Adoptive (methods)
• K562 Cells
• Lymphocytes (immunology, metabolism, physiology)
• Mice
• Mice, Transgenic
• Neoplasms (genetics, immunology, metabolism, pathology, therapy)
• Receptors, Antigen, T-Cell (genetics, metabolism)
• T-Cell Antigen Receptor Specificity (genetics)
• Transfection
• Xenograft Model Antitumor Assays