RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia

• Published in: Haematologica (Roma) Vol. 97; no. 10; pp. 1539 - 1547
• Main Authors: SNAUWAERT, Sylvia, VANHEE, Stijn, LECIERCQ, Georges, THIELEMANS, Kris, KERRE, Tessa, VANDEKERCKHOVE, Bart, GOETGELUK, Glenn, VERSTICHEL, Greet, VAN CAENEGHEM, Yasmine, VELGHE, Imke, PHILIPPE, Jan, BERNEMAN, Zwi N, PLUM, Jean, TAGHON, Tom
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01.10.2012
• Subjects: Adult; Aged; Animals; Antigens, CD34 - metabolism; Biological and medical sciences; Cell Cycle; Cell Line, Tumor; Disease Models, Animal; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - immunology; Extracellular Matrix Proteins - metabolism; Female; Gene Expression Regulation, Leukemic; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - metabolism; Humans; Hyaluronan Receptors - genetics; Hyaluronan Receptors - immunology; Hyaluronan Receptors - metabolism; Immunophenotyping; Immunotherapy; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocyte Activation - immunology; Male; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - metabolism; Original and Brief Reports; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Young Adult; Acute myelogenous leukemia; Receptor for hyaluronic acid mediated motility; Cell therapy; Hematology; Targeted therapy; Stem cell; leukemic stem cell; Malignant hemopathy; HMMR; RHAMM; Cell immunotherapy; Antigen; Treatment; acute myeloid leukemia; cell therapy and immunotherapy; Cancer
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2012.065581

Criteria for good candidate antigens for immunotherapy of acute myeloid leukemia are high expression on leukemic stem cells in the majority of patients with acute myeloid leukemia and low or no expression in vital tissues. It was shown in vaccination trials that Receptor for Hyaluronic Acid Mediated Motility (RHAMM/HMMR) generates cellular immune responses in patients with acute myeloid leukemia and that these responses correlate with clinical benefit. It is not clear however whether this response actually targets the leukemic stem cell, especially since it was reported that RHAMM is expressed maximally during the G2/M phase of the cell cycle. In addition, tumor specificity of RHAMM expression remains relatively unexplored. Blood, leukapheresis and bone marrow samples were collected from both acute myeloid leukemia patients and healthy controls. RHAMM expression was assessed at protein and mRNA levels on various sorted populations, either fresh or after manipulation. High levels of RHAMM were expressed by CD34(+)CD38(+) and CD34(-) acute myeloid leukemia blasts. However, only baseline expression of RHAMM was measured in CD34(+)CD38(-) leukemic stem cells, and was not different from that in CD34(+)CD38(-) hematopoietic stem cells from healthy controls. RHAMM was significantly up-regulated in CD34(+) cells from healthy donors during in vitro expansion and during in vivo engraftment. Finally, we demonstrated an explicit increase in the expression level of RHAMM after in vitro activation of T cells. RHAMM does not fulfill the criteria of an ideal target antigen for immunotherapy of acute myeloid leukemia. RHAMM expression in leukemic stem cells does not differ significantly from the expression in hematopoietic stem cells from healthy controls. RHAMM expression in proliferating CD34+ cells of healthy donors and activated T cells further compromises RHAMM-specific T-cell-mediated immunotherapy.