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

SYLVIA SNAUWAERT (UGent) , Stijn Vanhee (UGent) , Glenn Goetgeluk (UGent) , Greet Verstichel (UGent) , Yasmine Van Caeneghem (UGent) , Imke Velghe (UGent) , Jan Philippé (UGent) , Zwi N Berneman, Jean Plum (UGent) , Tom Taghon (UGent) , et al.
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Abstract
Background : 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. Design and Methods : 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. Results : 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. Conclusions : 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.
Keywords
leukemic stem cell, acute myeloid leukemia, cell therapy and immunotherapy, HMMR, RHAMM

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MLA
SNAUWAERT, SYLVIA, Stijn Vanhee, Glenn Goetgeluk, et al. “RHAMM/HMMR (CD168) Is Not an Ideal Target Antigen for Immunotherapy of Acute Myeloid Leukemia.” HAEMATOLOGICA-THE HEMATOLOGY JOURNAL 97.10 (2012): 1539–1547. Print.
APA
SNAUWAERT, S., Vanhee, S., Goetgeluk, G., Verstichel, G., Van Caeneghem, Y., Velghe, I., Philippé, J., et al. (2012). RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, 97(10), 1539–1547.
Chicago author-date
SNAUWAERT, SYLVIA, Stijn Vanhee, Glenn Goetgeluk, Greet Verstichel, Yasmine Van Caeneghem, Imke Velghe, Jan Philippé, et al. 2012. “RHAMM/HMMR (CD168) Is Not an Ideal Target Antigen for Immunotherapy of Acute Myeloid Leukemia.” Haematologica-the Hematology Journal 97 (10): 1539–1547.
Chicago author-date (all authors)
SNAUWAERT, SYLVIA, Stijn Vanhee, Glenn Goetgeluk, Greet Verstichel, Yasmine Van Caeneghem, Imke Velghe, Jan Philippé, Zwi N Berneman, Jean Plum, Tom Taghon, Georges Leclercq, Kris Thielemans, Tessa Kerre, and Bart Vandekerckhove. 2012. “RHAMM/HMMR (CD168) Is Not an Ideal Target Antigen for Immunotherapy of Acute Myeloid Leukemia.” Haematologica-the Hematology Journal 97 (10): 1539–1547.
Vancouver
1.
SNAUWAERT S, Vanhee S, Goetgeluk G, Verstichel G, Van Caeneghem Y, Velghe I, et al. RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. HAEMATOLOGICA-THE HEMATOLOGY JOURNAL. 2012;97(10):1539–47.
IEEE
[1]
S. SNAUWAERT et al., “RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia,” HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, vol. 97, no. 10, pp. 1539–1547, 2012.
@article{3033317,
  abstract     = {Background : 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. 
Design and Methods : 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. 
Results : 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. 
Conclusions : 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.},
  author       = {SNAUWAERT, SYLVIA and Vanhee, Stijn and Goetgeluk, Glenn and Verstichel, Greet and Van Caeneghem, Yasmine and Velghe, Imke and Philippé, Jan and Berneman, Zwi N and Plum, Jean and Taghon, Tom and Leclercq, Georges and Thielemans, Kris and Kerre, Tessa and Vandekerckhove, Bart},
  issn         = {0390-6078},
  journal      = {HAEMATOLOGICA-THE HEMATOLOGY JOURNAL},
  keywords     = {leukemic stem cell,acute myeloid leukemia,cell therapy and immunotherapy,HMMR,RHAMM},
  language     = {eng},
  number       = {10},
  pages        = {1539--1547},
  title        = {RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia},
  url          = {http://dx.doi.org/10.3324/haematol.2012.065581},
  volume       = {97},
  year         = {2012},
}

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