1. Leukemia Research 34 (2010) 850–851
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Leukemia Research
journal homepage: www.elsevier.com/locate/leukres
Guest editorial
Immunogenic antigens as therapeutic targets against myeloid
leukaemic cells
The number of immunogenic antigens in malignant myeloid solid tumour entities as well as CML progenitor cells, SPAG9 is an
diseases like chronic myeloid leukaemia (CML), acute myeloid interesting target structure for a lot of patients with different malig-
leukaemia (AML) and myelodysplastic syndrome (MDS) increases. nancies. Therefore, SPAG9 fulfils several characteristics of the ideal
Therefore, plenty of leukaemia-associated antigens (LAAs) like target antigen: It is described as malignancy-restricted, present in
BAGE, BCR-ABL, OFA-iLRP, FLT3-ITD, G250, hTERT, PRAME, a majority of patients, expressed on the cell surface, critical for
proteinase 3, RHAMM and WT-1 that elicit CD8-positive T cell- tumour cell survival and humoral immune responses are shown.
responses have been characterized and interestingly, most of them However, the induction of specific CD8-positive T cell-responses
are linked to cell cycle or proliferation [1]. As a consequence, clin- against SPAG9 has to be shown.
ical vaccination trials were inaugurated to target some of these Several immunotherapeutic approaches show the efficacy in
LAAs (BCR-ABL, RHAMM, proteinase 3 and WT-1) and they lead to eliminating minimal residual disease. The success of allogeneic
encouraging immunological and clinical results for patients with haematopoietic stem cell transplantation (HSCT) and donor lym-
AML, CML, MDS or multiple myeloma [2–6]. Due to the motivating phocyte infusion (DLI) is based on the GVL-effect mediated by
results in first clinical trials the question is whether it is necessary to cytotoxic T cells. Their target structures are minor histocompati-
identify further immunogenic target structures or just focus on the bility antigens (mHAg) restricted to haematopoietic cells as well as
optimal clinical setting and conditions. Indeed, not all of the iden- LAAs. Therefore, in patients with CML it could be shown that clin-
tified LAAs seem to be optimal target structures: Only some of the ical responses were correlated with the presence of PR1-specific
known LAAs are expressed in different tumour entities in a high fre- CD8-positive T cells after allogeneic HSCT or therapy with INF-
quency, i.e. WT-1, RHAMM and PRAME. Moreover, only the antigens alpha [10]. Results of several clinical vaccination trials against
RHAMM and WT-1 induce both cellular and also humoral immune LAAs showed efficacy in inducing T cells against minimal resid-
responses [7,8]. However, the coexistence of immune responses ual disease. In a phase 3 study with 320 AML patients, using a
of CD4-positive T cells and also CD8-positive T cells against LAAs post-consolidation immunotherapy with interleukin-2 (IL-2) and
might be very important for an effective anti-tumour response and histamine dihydrochloride (HDC), Brune et al. could show an
tumour cell lysis. In conclusion, the search for the optimal immuno- improved leukaemia-free survival of adult patients with acute
genic structure, clinical setting and the appropriate adjuvant has to myeloid leukaemia (AML) in complete remission [11]. These efforts
be continued to improve responses in clinical trials. demonstrate the important role of T cell orchestration and LAAs
The sperm-associated antigen 9 (SPAG9) is a new antigen with a as their potential target structures and underline that malignant
very high frequency of humoral immune responses in CML patients haematological diseases are candidates for immunotherapeutic
[9]: More than 85% of CML patients in chronic phase showed posi- approaches. Eliminating minimal residual disease in patients with
tive serological immune reactions against this antigen. SPAG9 was myeloid diseases is difficult and an important challenge to improve
previously characterized as a Cancer/Testis-antigen (CT-antigen) overall survival and cure rate. Immunotherapeutic approaches
which is involved in MAPK signalling pathway. The protein is highly expand the portfolio of leukaemia treatment by targeting LAAs.
expressed in epithelial ovarian cancer, renal cell carcinoma, breast Moreover, even in AML or MDS the treatment options especially
carcinoma, cervical cancer patients and thyroid cancer. However, for elderly patients are often restricted to palliative therapies and
SPAG9 is also expressed in a high frequency in CML – 88% of 120 immunotherapies are options with low toxicity and side effects.
CML patients showed mRNA expression of SPAG9.
An elegant way to eliminate leukaemic progenitor cells would
be using monoclonal antibodies that recognize antigens which are 1. Summary
selectively expressed on the surface of malignant cells. Targeting
cell surface molecules by antibodies is very effective as demon- SPAG9 is a further new antigen that might be a candidate for
strated by drugs like rituximab in lymphomas or gemtuzumab clinical use. In particular the high frequency of mRNA expression in
ozogamicin in AML. As the SPAG9 protein is also expressed on the different solid tumours and haematological malignancies is a pre-
cell surface of tumour cells, this antigen might be a feasible tar- requisite for a potentially wide use. Most of the tested CML patients
get for antibody-directed approaches. The expression frequency showed humoral immune responses against SPAG9. Nevertheless,
is an important manner for potential clinical relevance and use- specific CD8-positive T cell-responses and clinical efficacy analogue
fulness. As SPAG9 is expressed in a high frequency in different to the targets RHAMM or WT-1 have to be shown.
0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.leukres.2010.03.013

2. Guest editorial / Leukemia Research 34 (2010) 850–851 851
Conflict of interest statement [7] Greiner J, Li L, Ringhoffer M, Barth TF, Giannopoulos K, Guillaume P, et al.
Identification and characterization of epitopes the receptor for hyaluronic
acid-mediated motility (RHAMM/CD168) recognized by CD8+ T cells of HLA-
No potential conflicts of interest were disclosed. A2-positive patients with acute myeloid leukemia. Blood 2005;106(August
(3)):938–45.
Acknowledgements [8] Elisseeva OA, Oka Y, Tsuboi A, Ogata K, Wu F, Kim EH, et al. Humoral immune
responses against Wilms tumor gene WT1 product in patients with hematopoi-
etic malignancies. Blood 2002;99(9):3272–9.
We would like to thank Ms. Götz for critically reading the [9] Kanojia D, Garg M, Saini S, Agarwal S, Kumar R, Suri A. Sperm associated antigen
manuscript. The work was supported by a generous grant from the 9 expression and humoral response in chronic myeloid leukemia. Leuk Res
2010;34(7):858–63.
German José Carreras Leukemia Foundation (DJCLS R09/13). [10] Molldrem JJ, Lee PP, Wang C, Felio K, Kantarjian HM, Champlin RE, et al. Evi-
dence that specific T lymphocytes may participate in the elimination of chronic
References myelogenous leukemia. Nat Med 2000;6(9):1018–23.
[11] Brune M, Castaine S, Catalano J, Gehlsen K, Ho AD, Hofmann WK, et al. Improved
leukemia-free survival after postconsolidation immunotherapy with histamine
[1] Greiner J, Bullinger L, Guinn BA, Dohner H, Schmitt M. Leukemia-associated
dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a ran-
antigens are critical for the proliferation of acute myeloid leukemia cells. Clin
domized phase 3 trial. Blood 2006;108(July (1)):88–96.
Cancer Res 2008;14(22):7161–6.
[2] Schmitt M, Schmitt A, Rojewski MT, Chen J, Giannopoulos K, Fei F, et al.
RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, Susanne Hofmann
myelodysplastic syndrome, and multiple myeloma elicits immunologic and Jochen Greiner ∗
clinical responses. Blood 2008;111(3):1357–65.
[3] Greiner J, Schmitt A, Giannopoulos K, Rojewski MT, Götz M, Funk I, et al. Department of Internal Medicine III,
High dose RHAMM-R3 peptide vaccination for patients with acute myeloid University Hospital of Ulm, Albert-Einstein-Allee 23,
leukemia (AML), myelodysplastic syndrome (MDS) and multiple myeloma 89081 Ulm, Germany
(MM). Haematologica 2010 [Epub ahead of print].
[4] Rezvani K, Yong AS, Mielke S, Savani BN, Musse L, Superata J, et al. Leukemia-
∗ Corresponding author. Tel.: +49 731 500 45709;
associated antigen-specific T-cell responses following combined PR1 and
WT1 peptide vaccination in patients with myeloid malignancies. Blood fax: +49 731 500 45750.
2008;111(1):236–42.
[5] Keilholz U, Letsch A, Busse A, Asemissen AM, Bauer S, Blau IW, et al. A clinical
E-mail address: Jochen.greiner@uniklinik-ulm.de
and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide (J. Greiner)
vaccination in patients with AML and MDS. Blood 2009;113(June (26)):6541–8.
[6] Rojas JM, Knight K, Wang L, Clark RE. Clinical evaluation of BCR-ABL pep-
16 February 2010
tide immunisation in chronic myeloid leukaemia: results of the EPIC study.
Leukemia 2007;21(11):2287–95. Available online 31 March 2010