Abstract
The anaplastic lymphoma kinase (ALK) is recognized by the immune system as a tumor antigen, and preclinical evidence suggests that ALK-rearranged NSCLCs can also be successfully targeted immunologically using vaccine-based approaches. In contrast to ALK-rearranged lymphomas, the frequency and clinical significance of spontaneous ALK immune responses in patients with ALK-rearranged NSCLCs are largely unknown. We developed an enzyme-linked immunosorbent assay (ELISA) to measure anti-ALK antibody levels and mapped specific peptide epitope sequences within the ALK cytoplasmic domain in patients with non-small cell lung cancer. The ELISA method showed good correlation with ALK antibody titers measured with a standard immunocytochemical approach. Strong anti-ALK antibody responses were detected in 9 of 53 (17.0%) ALK-positive NSCLC patients and in 0 of 38 (0%) ALK-negative NSCLC patients (P<0.01), and the mean antibody levels were significantly higher in ALK-positive than in ALK-negative NSCLC patients (P=0.02). Across individual patients, autoantibodies recognized different epitopes in the ALK cytoplasmic domain, most of which clustered outside the tyrosine kinase domain. Whether the presence of high ALK autoantibody levels confers a more favorable prognosis in this patient population warrants further investigation.
Highlights
About 3-7% of non-small cell lung cancers (NSCLC) harbor rearrangements in the anaplastic lymphoma kinase (ALK) gene [1]
High levels of ALK antibodies were detected in 17.0% of ALK-positive NSCLC patients by a new quantitative enzyme-linked immunosorbent assay (ELISA) technique developed for the measurement of ALK antibodies in patient serum
These patients had antibody levels comparable to levels detected in ALK-positive anaplastic large cell lymphoma (ALCL) patients
Summary
About 3-7% of non-small cell lung cancers (NSCLC) harbor rearrangements in the anaplastic lymphoma kinase (ALK) gene [1]. Among crizotinib-resistant patients, the objective response rate to the FDA-approved next-generation ALK www.impactjournals.com/oncotarget inhibitors ceritinib and alectinib is 48-56%, with a mPFS of only 7.0-8.1 months [7,8,9] because of the invariable development of drug resistance [10, 11]. A potential alternative strategy for treating ALK-positive cancers is to exploit the natural immune responses against tumor cells expressing ALK protein. Immune system recognition of the ALK protein has been demonstrated in patients with ALK-positive anaplastic large cell lymphoma (ALCL). ALK-specific tumor-reactive T-cells can be detected in the blood of ALK-positive ALCL patients, but not in healthy volunteers [13]. We have shown that high ALK autoantibody titers in ALK-positive ALCL patients are associated with a favorable prognosis [14]
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