Immune response to the ALK oncogenic tyrosine kinase in patients with anaplastic large-cell lymphoma

Abstract

Oncogenic anaplastic lymphoma kinase (ALK) fusion proteins (nucleophosmin–ALK [NPM-ALK] and other variants) are expressed in many cases of anaplastic large-cell lymphoma (ALCL) but are absent from normal tissues. The possibility that ALK proteins are immunogenic was investigated with the use of an immunocytochemical technique to screen plasma from ALK-positive ALCL on transfectants expressing ALK proteins and by an in vitro kinase assay. Circulating antibodies against NPM-ALK protein were present in all ALK-positive ALCL patients (11 out of 11 cases) studied while 10 patients also had antibodies recognizing normal ALK protein. Weak antibodies reactive with NPM-ALK (which may represent anti-NPM autoantibodies) were detected by the in vitro kinase assay in 3 of the 10 control samples (but not by immunocytochemistry). The presence of anti-ALK antibodies may be relevant to the relatively good prognosis of ALK-positive ALCL. The immunocytochemical technique for detecting anti-ALK activity is simple and semiquantative and may provide a means of detecting B-cell responses to other tumor-associated molecules.

Crizotinib induces apoptosis and gene expression changes in ALK+ anaplastic large cell lymphoma cell lines; brentuximab synergizes and doxorubicin antagonizes

“…6 ALK+ ALCL elicits an antibody response that is detectable in patient serum and has been postulated to be involved in relatively good outcomes for the disease. 68 Vinblastine, in addition to exhibiting cytotoxicity, is an immunomodulator that augments dendritic cell function and possibly immune response to tumor cells. 69 In our study, vinblastine downregulated a number of genes analogous to the effect of crizotinib, but these did not achieve significance.…”

Efficacy of nivolumab in a patient with systemic refractory ALK+ anaplastic large cell lymphoma

“…Anaplastic lymphoma kinase (ALK) fusions can elicit an immune response in patients with ALK+ anaplastic large cell lymphoma (ALCL) as demonstrated by the detection of antibodies against ALK as well as cellular immune responses against tumor cells, suggesting a role of the immune system in the control of this disease. 1 Despite the high response rates obtained with diverse chemotherapy regimens, 20-40% of patients with ALK+ ALCL suffer relapse, in some cases on multiple occasions. 2 Targeted agents, including brentuximab vedotin and ALK inhibitors, have shown remarkable efficacy in patients who have received several previous lines of treatment.…”

Anaplastic large cell lymphoma: pathological, molecular and clinical features

“…These findings suggest that lymphomas expressing variant ALK fusion proteins can be clustered with classical ALCL expressing NPM–ALK as a single entity (ALK‐positive ALCL) and regarded as a separate entity with a better prognosis than ALK‐negative ALCL (Falini et al , 1999b). Whether the good prognosis of ALK‐positive lymphomas is somehow related to the ability of patients to generate an antibody response to the ALK protein (Pulford et al , 2000), or to the higher proliferative activity of ALK‐positive compared with the ALK‐negative ALCL (Leoncini et al , 2000) remains to be clarified.…”