IntroductionThere is increasing evidence of the importance of the immune system in cancer development and control. 1,2 Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) in children and adolescents represents an ideal tumor model to study the existence and impact of a tumor-specific immune response. First, all tumor cells express high levels of ALK in the form of ALK fusion proteins resulting from oncogenic chromosomal translocations. In contrast to many other tumor-associated antigens (TAAs), ALK fusion proteins exert an essential role in lymphomagenesis and the survival of the tumor cells, therefore representing real oncoantigens. 3 The most common ALK fusion protein is nucleophosmin (NPM)-ALK resulting from the t(2;5)(p23;q35) translocation occurring in 90% of ALK-positive ALCLs. 4 Second, the normal tissue distribution of ALK is restricted to a few scattered neurons in the central nervous system, 5 thus permitting specific targeting of ALK while minimizing problems with autoimmunity. Third, immunity to ALK may be implicated in the control of ALK-positive ALCLs. Antibodies against ALK and cytotoxic T-cell and CD4 T-helper responses to ALK have been detected in patients with ALK-positive ALCLs both at the time of diagnosis and during remission. 6-10 Furthermore, murine studies have identified ALK as an ideal tumor antigen for vaccination-based therapies. 11The current study was therefore performed in a large cohort of uniformly treated children and adolescents with ALK-positive ALCLs to investigate (1) the prevalence of a preexisting antibody response to ALK and (2) whether the strength of the antibody response correlates with parameters of tumor dissemination and the risk of relapse. Methods PatientsA total of 236 patients from the Berlin-Frankfurt-Muenster group study NHL-BFM95 study with a diagnosis of ALCL and German patients enrolled in the European inter-group trial ALCL99 between April 1996 and November 2007 were eligible for this study. Both studies were approved by the institutional Ethics committee of the primary investigator of the BFM group (A.R.) at Justus-Liebig-University. NPM-ALK positivity of the ALCL was confirmed by at least one of the following: presence of NPM-ALK mRNA, positive 2-color fluorescence in situ hybridization for the t(2;5)(p23;q35) NPM-ALK translocation, and/or immunolabeling studies to show the presence of nuclear and cytoplasmic ALK in the tumor cells.The treatment strategy was based on protocol NHL-BFM90, as described previously. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From system) and the involvement of at-risk organs. 14 Staging procedures included bone marrow (BM) aspiration cytology and a spinal tap. Detection and quantification of submicroscopic amounts of circulating tumor cells in BM or blood at diagnosis were carried out by quantitative real-time polymerase chain reaction (PCR) for NPM-ALK transcripts as previously described. 15 Serum and/or plasma samples were obtained at the time of diagnosis from 95 patie...

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) has a good prognosis compared to ALK-negative ALCL, possibly as a result of the immune recognition of the ALK proteins. The aim of our study was to investigate the presence of both a B and cytotoxic T cell (CTL) response to ALK in ALK-positive ALCL. We confirmed the presence of an antibody response to ALK in all 9 ALK-positive ALCL patients investigated. An ELISpot assay was used to detect a c-interferon (IFN) T cell response after short term culture of mononuclear blood cells with 2 ALK-derived HLA-A*0201 restricted peptides: ALKa and ALKb. A significant c-IFN response was identified in all 7 HLA-A*0201-positive ALK-positive ALCL patients but not in ALKnegative ALCL patients (n 5 2) or normal subjects (n 5 6). CTL lines (>95% CD8-positive) raised from 2 ALK-positive ALCL patients lysed ALK-positive ALCL derived cell lines in a MHCClass I restricted manner. This is the first report of both a B cell and CTL response to ALK in patients with ALK-positive ALCL. This response persisted during long-term remission. The use of modified vaccinia virus Ankara (MVA) to express ALK is also described. Our findings are of potential prognostic value and open up therapeutic options for those ALK-positive patients who do not respond to conventional treatment. ' 2005 Wiley-Liss, Inc.

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