The candidate immunotherapeutical target, the receptor for hyaluronic acid-mediated motility, is associated with proliferation and shows prognostic value in B-cell chronic lymphocytic leukemia

Giannopoulos, Krzysztof; Mertens, Daniel; Bühler, Andreas; Barth, Thomas F.E.; Idler, Irina; Möller, Peter; Kröber, Alexander; Greiner, Jochen; Chocholska, Sylwia; Dmoszyńska, Anna; Roliński, Jacek; Döhner, Hartmut; Stilgenbauer, Stephan; Schmitt, Michael

doi:10.1038/leu.2008.338

Cited by 33 publications

(34 citation statements)

References 24 publications

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“…14 Recently, we described the increased expression of RHAMM in high-risk CLL patients (characterized by unmutated IgVH gene status as well as del11q and del17p). 15 Moreover, we showed that R3-primed CD8 þ T cells were able to lyse RHAMM þ CLL target cells, thereby providing additional validation of RHAMM as a preferred target for immunotherapy in CLL. 15 We also described encouraging results from a peptide vaccination trial based on R3, showing clinical as well as immunological responses in a heterogeneous group of hematological patients suffering from acute myeloid leukemia, myelodysplastic syndrome or multiple myeloma, 16 conditions in which RHAMM is also overexpressed.…”

Section: Introductionmentioning

confidence: 91%

Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia

et al. 2010

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The receptor for hyaluronic acid-mediated motility (RHAMM) is a tumor-associated antigen in chronic lymphocytic leukemia (CLL). CD8 þ T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)-A2, effectively lyse RHAMM þ CLL cells. Therefore, we initiated a phase I clinical trial of R3 peptide vaccination. Six HLA-A2 þ CLL patients were vaccinated four times at biweekly intervals with the R3 peptide (ILSLELMKL; 300 lg per dose) emulsified in incomplete Freund's adjuvant; granulocyte-macrophage colony stimulating factor (100 lg per dose) was administered concomitantly. Detailed immunological analyses were conducted throughout the course of peptide vaccination. No severe adverse events greater than CTC I1 skin toxicity were observed. Four patients exhibited reduced white blood cell counts during vaccination. In five of six patients, R3-specific CD8 þ T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in four of five patients using enzyme-linked immunosorbent spot (ELISpot) assays. In patients with clinical responses, we found increased frequencies of R3-specific CD8 þ T cells that expressed high levels of CD107a and produced both interferon-c and granzyme B in response to antigen challenge. Interestingly, vaccination was also associated with the induction of regulatory T cells in four patients. Thus peptide vaccination in six CLL patients was safe and could elicit to some extent specific CD8 þ T-cell responses against the tumor antigen RHAMM.

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Section: Introductionmentioning

confidence: 91%

Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia

et al. 2010

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“…Recently, we characterized leukemia antigen RHAMM as a molecule www.fhc.viamedica.pl expressed in high frequency of CLL patients without measurable expression in healthy volunteers [10]. We further found association of antigen RHAMM expression with proliferation potential (defined by Ki-67 expression in lymph nodes) as well as functional dependence on CD40-CD40L pathway, which seems to play an important role in the pathogenesis of CLL [11]. Most recently, we completed the first vaccination trial with the peptide R3 which represented the most immunologic epitope of antigen RHAMM in CLL patients [12].…”

Section: Introductionmentioning

confidence: 92%

Peptide vaccination induces profound changes in the immune system in patients with B-cell chronic lymphocytic leukemia

Giannopoulos¹,

Własiuk²,

Dmoszyńska³

et al. 2011

Folia Histochem Cytobiol.

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Abstract:Although the immune status of chronic lymphocytic leukemia (CLL) patients is mostly characterized by immunosuppression, there is an accumulation of in vivo (graft-versus-leukemia effect) and in vitro (spontaneous remissions after infections) data that indicates that CLL might be effectively targeted by T-cell based immunotherapy. Recently, we characterized receptor for hyaluronic acid mediated motility (RHAMM) as a preferential target for immunotherapy of CLL. We also completed a RHAMM-derived peptide vaccination phase I/II clinical trial in CLL. Here, we present a detailed immunological analysis of six CLL patients vaccinated with HLA-A2 restricted RHAMM-derived epitope R3 (ILSLELMKL). Beside effective induction of R3-specific cytotoxic T-cells, peptide vaccination caused profound changes in different T-cell subsets as well as cytokines. We present longitudinal analyses of Th17, CD8

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“…6,11 High expression of RHAMM has been correlated with a poor prognosis in patients with various types of solid tumors and hematologic malignancies such as B-cell chronic lymphocytic leukemia, multiple myeloma and AML. [12][13][14][15][16] RHAMM-specific CD8 + T cells were detected in patients diagnosed with AML and chronic myeloid leukemia. [17][18][19] Using a lymphoma mouse model, anti-tumor activity mediated by CD4 + T cells was observed after vaccination with RHAMM mRNA-transfected dendritic cells.…”

Section: Cd38mentioning

confidence: 99%

“…7,26,30,[33][34][35] In addition, other studies demonstrated a direct or indirect correlation between RHAMM and proliferation, both in malignant cells and in physiological nonhomeostatic settings such as wound healing and regeneration. 14,32,[35][36][37][38] It is not, therefore, surprising that in a variety of hematologic and solid malignancies, RHAMM overexpression was described to be correlated with a poor prognosis. [12][13][14][15][16] We strongly believe that this correlation is not only due to the function of RHAMM in cell motility and, consequently, the invasiveness of tumor cells, 30 but can also be attributed to RHAMM being a genuine 'proliferation marker'.…”

Section: Cd38mentioning

confidence: 99%

“…14,32,[35][36][37][38] It is not, therefore, surprising that in a variety of hematologic and solid malignancies, RHAMM overexpression was described to be correlated with a poor prognosis. [12][13][14][15][16] We strongly believe that this correlation is not only due to the function of RHAMM in cell motility and, consequently, the invasiveness of tumor cells, 30 but can also be attributed to RHAMM being a genuine 'proliferation marker'. The major drawback of the proliferationdependent expression of RHAMM is that non-malignant, actively dividing cells tend to express high levels of RHAMM too.…”

Section: Cd38mentioning

confidence: 99%

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

et al. 2012

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The online version of this article has a Suppplementary Appendix. BackgroundCriteria 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 MethodsBlood, 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. ResultsHigh 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. ConclusionsRHAMM 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.

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The candidate immunotherapeutical target, the receptor for hyaluronic acid-mediated motility, is associated with proliferation and shows prognostic value in B-cell chronic lymphocytic leukemia

Cited by 33 publications

References 24 publications

Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia

Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia

Peptide vaccination induces profound changes in the immune system in patients with B-cell chronic lymphocytic leukemia

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

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