CD4 T-Helper Responses to the Anaplastic Lymphoma Kinase (ALK) Protein in Patients with ALK-Positive Anaplastic Large-Cell Lymphoma

Abstract

We have previously shown both humoral and CTL responses to anaplastic lymphoma kinase (ALK) in patients with ALKpositive anaplastic large-cell lymphoma (ALCL). However, because CD4 + T-helper (Th) cells also play a vital role in developing and maintaining tumor immunity, we investigated the presence of a CD4 + Th response in ALK-positive ALCL. Using an IFN-; ELISPOT assay, we identified two ALK-derived DRB1-restricted 24-mer promiscuous peptides, ALK1 278-301 and ALK2 , as being immunogenic in six ALK-positive ALCL patients but not in two ALK-negative ALCL patients or five normal subjects. A significant interleukin-4 response to the ALK peptides was detected in only one ALK-positive patient.

Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase–positive anaplastic large cell lymphoma with tumor dissemination and relapse risk

“…ALK-positive ALCL, therefore, constitutes an excellent disease model to study the impact on disease progression and prognosis of a preexisting immune response to an oncoantigen. Although our initial study and subsequent reports describe both B-and T-cell immune responses to ALK in patients with ALK-positive ALCL at diagnosis, 6,8,10,17 the present study provides the first clinical evidence that the preexisting antibody response to ALK correlates inversely with tumor dissemination and has prognostic value for patients with this malignancy.…”

“…ALK-positive ALCL, therefore, constitutes an excellent disease model to study the impact on disease progression and prognosis of a preexisting immune response to an oncoantigen. Although our initial study and subsequent reports describe both B-and T-cell immune responses to ALK in patients with ALK-positive ALCL at diagnosis, 6,8,10,17 the present study provides the first clinical evidence that the preexisting antibody response to ALK correlates inversely with tumor dissemination and has prognostic value for patients with this malignancy.We detected in our 95 patients a significant inverse correlation between the titer of the antibody response against ALK and the following parameters: disease stage and the dissemination of the disease to BM, blood, and visceral organs. These results, obtained from samples taken at diagnosis before treatment, indicate that the titer of the anti-ALK antibody response does not just reflect the extent of the disease.…”

“…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][7][8][9][10] Furthermore, murine studies have identified ALK as an ideal tumor antigen for vaccination-based therapies. 11 The 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.…”

Kinetics of humoral response to ALK and its relationship with minimal residual disease in pediatric ALCL

“…The titer and kinetics of anti-ALK antibody may also Letters to the Editor represent prognostic markers in ALCL, but they need further investigation in the context of a larger series of patients and in conjunction with additional immunological parameters. The increasing amount of knowledge on several immunological aspects of ALCL yielded recently, including evidence of in vivo anti-ALCL immune reactivity, 7,8 warrants the design of vaccination trials to be tested in ALCL patients.…”

“…6 Further, pharmacokinetic studies with GO have reported large inter-subject variability in both pediatric and adult patients. 7,8 In the present study, we undertook a comprehensive analysis of CD33 expression, including polymorphisms in the CD33 gene, and correlated the results to GO response as measured by changes in minimal residual disease (MRD) levels.…”