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01.09.2009 | Focussed Research Review | Ausgabe 9/2009

Cancer Immunology, Immunotherapy 9/2009

Tumour antigen-targeted immunotherapy for chronic myeloid leukaemia: is it still viable?

Zeitschrift:
Cancer Immunology, Immunotherapy > Ausgabe 9/2009
Autoren:
Catherine L. Riley, Morgan G. Mathieu, Richard E. Clark, Stephanie E. B. McArdle, Robert C. Rees
Wichtige Hinweise
C. L. Riley and M. G. Mathieu are joint first authors and have contributed equally to this paper.
This paper is a Focussed Research Review from the meeting which took place 28–29 May 2008 in Nottingham, UK, celebrating the contribution of Prof. I. A. “Tony” Dodi (+29.1.2008) to the EU project “Network for the identification and validation of antigens and biomarkers in cancer and their application in clinical tumour immunology (ENACT)”.
This review is dedicated to Prof. Tony Dodi (who passed away suddenly on 29 January 2008) and is written by colleagues who worked with him on research collaborations for more than 10 years. The paper deals with an area of research that Tony dedicated his working life to, that of leukaemia and immunotherapy. His contribution to this research was immense and he will be remembered for his drive, enthusiasm and passion for research excellence, which was infectious. Catherine Riley was Tony’s graduate student who successfully completed her doctorate degree, owing much to his wise direction and advice.

Abstract

In haematological cancers, malignant cells circulate in the blood and lymphatic system. This may make leukaemic cells easier to target by immunotherapy than in other types of cancer. Various immunotherapy strategies have been trialled in several leukaemias including chronic myeloid leukaemia (CML) and in general, these have been aimed at targeting tumour-associated antigens (TAA). There are numerous TAA expressed by CML patients including WT1, proteinase 3, BCR-ABL and HAGE amongst others. The immunogenicity of the CML-specific tumour antigen, BCR-ABL, has been the subject of much debate and its role in the development of the disease and its unique sequence spanning the breakpoint region make it an ideal target for immunotherapy. However, there are a limited number of immunogenic epitopes across the junctional region, which are restricted to only a few HLA types, namely A2, A3 and B7 (Clark et al. in Blood 98:2887–2893, 2001). The second CML-associated antigen is the helicase antigen HAGE, a cancer-testis antigen found to be over-expressed in more than 50% of myeloid leukaemias (Adams et al. in Leukaemia 16:2238–2242, 2002). Very little is known about the function of this antigen and its significance to CML. However, its membership of the DEAD-box family of ATP-dependent RNA helicases and the involvement of other members of this family in tumour cell proliferation (Eberle et al. in Br J Cancer 86:1957–1962, 2002; Yang et al. in Cell Signal 17:1495–504, 2005) suggest a crucial role in the RNA metabolism of tumour cells. For these reasons, HAGE also seems to be a good target for immunotherapy as it would be applicable for the majority of patients with CML. This review aims to discuss the potential of immunotherapy for the treatment of leukaemia, in particular CML, and the prospect of targeting three CML associated antigens: BCR, ABL and HAGE. During his career, Prof. Tony Dodi made a significant contribution in this area of leukaemia research, confirming the identity of immunogenic HLA-A3 and B7-restricted peptides as targets for CTL. Published, as a highlighted paper in Clark et al. (Blood 98:2887–2893, 2001), this study demonstrated the expression of MHC-peptide complexes on the surface of CML cells and the presence of tetramer-positive CTL activity in CML patients positive for these two HLA alleles. His drive and dedication for research excellence will be remembered by all who knew and worked with him.

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