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Assessment of neuronal autoantibodies in patients with small cell lung cancer treated with chemotherapy with or without ipilimumab.

ABSTRACT: Small-cell lung cancer (SCLC) is often associated with paraneoplastic syndromes. To assess the role of anti-neuronal autoantibodies (NAAs) as biomarkers of treatment outcome, we assessed NAAs in serial samples from SCLC patients treated with chemoimmunotherapy compared to chemotherapy alone. We evaluated 2 cohorts: in cohort 1 (C1), 47 patients received standard platinum/etoposide, and in cohort 2 (C2), 38 patients received ipilimumab, carboplatin and etoposide. Serum samples at baseline and subsequent time points were analyzed for the presence of NAAs. NAAs were detected at baseline in 25 patients (53.2%) in C1 and in 20 patients (52.6%) in C2 (most frequently anti-Sox1). NAA at baseline was associated with limited disease (75% vs 50%; p: 0.096) and better overall survival (15.1 m vs 11.7 m; p: 0.032) in C1. Thirteen patients (28.9%) showed 2 or more reactivities before treatment; this was associated with worse PFS (5.5 m vs 7.3 m; p: 0.005) in patients treated with chemoimmunotherapy. NAA titers decreased after therapy in 68.9% patients, with no differential patterns of change between cohorts. Patients whose NAA titer decreased after treatment, showed longer OS [18.5 m (95% CI: 15.8 - 21.2)] compared with those whose NAA increased [12.3 m (95% CI: 8.1 - 16.5; p 0.049)], suggesting that antibody levels correlate to tumor load. Our findings reinforce the role of NAAs as prognostic markers and tumor activity/burden in SCLC, warrant further investigation in their predictive role for immunotherapy and raise concern over the use of immunotherapy in patients with more than one anti-NAA reactivity.

SUBMITTER: Hardy-Werbin M

PROVIDER: S-EPMC5749672 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Assessment of neuronal autoantibodies in patients with small cell lung cancer treated with chemotherapy with or without ipilimumab.

Hardy-Werbin M M Arpí O O Taus A A Rocha P P Joseph-Pietras D D Nolan L L Danson S S Griffiths R R Lopez-Botet M M Rovira A A Albanell J J Ottensmeier C H CH Arriola E E

Oncoimmunology 20171127 2

Small-cell lung cancer (SCLC) is often associated with paraneoplastic syndromes. To assess the role of anti-neuronal autoantibodies (NAAs) as biomarkers of treatment outcome, we assessed NAAs in serial samples from SCLC patients treated with chemoimmunotherapy compared to chemotherapy alone. We evaluated 2 cohorts: in cohort 1 (C1), 47 patients received standard platinum/etoposide, and in cohort 2 (C2), 38 patients received ipilimumab, carboplatin and etoposide. Serum samples at baseline and sub ...[more]

PMID: 29308329

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Project description:ImportanceParaneoplastic neurological syndromes are associated with neuronal autoantibodies, and some of these autoantibodies are associated with neuropsychological symptoms. The most common underlying tumor is lung cancer. The association of neuronal autoantibodies with cognitive deficits has not been systematically investigated in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).ObjectiveTo assess the frequency of neuronal autoantibodies in patients with lung cancer and analyze their association with cognitive function.Design, setting, and participantsThis prospective, cross-sectional study included 167 patients with lung cancer (both SCLC and NSCLC) recruited at a single lung cancer center in Berlin, Germany, between June 2015 and April 2016. Detailed neuropsychological testing was performed in a carefully selected subgroup of 97 patients (from which patients with potential confounding factors were excluded). Investigators were blinded to patients' autoantibody status and cognitive test results. Data were analyzed from May 2016 to December 2019.Main outcomes and measuresPrevalence of neuronal autoantibodies and their association with cognitive impairment. The evaluation of autoantibodies as potential risk factors for cognitive impairment was performed using bayesian logistic regression models.ResultsAmong 167 patients with lung cancer (median age, 66.0 years [interquartile range, 59.0-72.0 years]; 105 men [62.9%]), 127 had NSCLC, and 40 had SCLC. Brain-directed autoantibodies were detected in 61 of 167 patients (36.5%); 33 patients (19.8%) had known autoantibodies and 28 patients (16.8%) had autoantibodies against currently unknown antigens that were detected through immunohistochemical analysis. Cognitive impairment was found in 65 of 97 patients (67.0%). Among patients with SCLC, the odds of cognitive impairment for those with any autoantibodies was 11-fold higher (odds ratio [OR], 11.0; 95% credible interval [CrI], 1.2-103.6) than that of autoantibody-negative patients, and the increased odds were independent of age, sex, and neurological deficit. Among patients with NSCLC, those with immunoglobin A autoantibodies targeting the N-methyl-d-aspartate receptor had a relevantly increased odds of verbal memory deficits (OR, 182.8; 95% CrI, 3.1-10 852.4). Autoantibodies against currently unknown antigens were also associated with increased odds of cognitive impairment (OR, 2.8; 95% CrI, 0.6-12.1).Conclusions and relevanceIn this prospective, cross-sectional study, more than one-third of patients with lung cancer had neuronal autoantibodies that were found to be associated with cognitive impairment. These autoantibodies might represent a potentially treatable mechanism of immune-mediated cognitive impairment among patients with lung cancer.

Project description:AimAccurate causality assessment (CA) of adverse events (AEs) is important in clinical research and routine clinical practice. The Naranjo scale (NS) used for CA lacks specificity, leading to a high rate of false positive causal associations. NS is a simple scale for CA; however, its limitations have reduced its popularity in favour of other scales. We therefore attempted to improvise the algorithm by addressing specific lacunae in NS.MethodsWe attempted to modify the existing NS by (a) changing the weightage given to certain responses, (b) achieving higher resolution to certain responses for delineating drug related and unrelated AEs and (c) modifying the slabs for classification of association as 'likely' and 'unlikely'. The new scale, named as the Sharma-Nookala-Gota (SNG) algorithm, was evaluated in a training set of 19 AEs in a tertiary care cancer hospital in western India, and further validated in a set of 104 AEs. Consensus of four physician opinion was taken as gold standard for comparison.ResultsOf the 19 AEs in the training set, 6 were described by the treating physician as 'not related' and 13 as related to the drug. The SNG algorithm had 100% concordance with physician opinion, whereas the NS had only 73.7% concordance. NS showed a tendency to misclassify AEs as 'related' when they were indeed 'not related'. In the validation set of 104 AEs, NS and SNG algorithms misclassified 30 and 2 AEs, respectively, leading to a concordance of 70.2% and 98.1%, respectively, with physician opinion.ConclusionDecisive modifications of the NS resulted in the SNG scale, with superior specificity while retaining sensitivity against the gold standard.Plain language summarySNG algorithm - A novel tool for causality assessment of adverse drug reactions Adverse events (AEs) can cause increased morbidity, hospitalisation, and even death. Hence it is essential to recognise AEs and to establish their correct causal relationship to a drug. Many causality assessment methods, scales and algorithms are available to assess the relationship between an AE and a drug. The Naranjo algorithm is most commonly employed in spite of its many drawbacks as it is simple to use. Concerns have been raised regarding the performance of the scale, and researchers have tried to answer them, but none of them could address all issues satisfactorily. We too experienced many problems while using it in our routine clinical practice and in clinical trials. For instance, the Naranjo scale is non-specific and shows a bias toward implicating the drug as the causal factor for AEs. This improper assessment has often led to drug discontinuation, thereby compromising the efficacy of treatment. Hence, we modified the existing Naranjo scale to a new one (the Sharma-Nookala-Gota - SNG algorithm) to address these shortcomings. We piloted the SNG causality assessment algorithm in patients suffering from AEs due to various drugs. The SNG algorithm was found to have good concordance with the physicians' assessment of causality. As a next step, we validated the SNG algorithm in patients receiving a standard drug combination of pemetrexed and carboplatin for lung cancer combination. Out of the 104 AEs observed in 65 patients, the SNG causality assessment algorithm showed good concordance (except in two cases) with the physicians' decision of causality assessment, while the Naranjo algorithm was not so successful. Hence, the SNG algorithm can be a better guide for causality assessment of AEs.

Dataset Information

Assessment of neuronal autoantibodies in patients with small cell lung cancer treated with chemotherapy with or without ipilimumab.

Publications

Assessment of neuronal autoantibodies in patients with small cell lung cancer treated with chemotherapy with or without ipilimumab.

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