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Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma.

ABSTRACT: BACKGROUND:Multipeptide vaccines for melanoma may cause inflammatory adverse events (IAE). We hypothesize that IAE are associated with a higher rate of immune response (IR) to vaccination and improved clinical outcomes. METHODS:Adult patients with resected, high-risk (stage IIB to IV) melanoma were vaccinated with a combination of 12 class I major histocompatibility complex (MHC)-restricted melanoma epitopes, and IAE were recorded. A separate category for hypopigmentation (vitiligo) was also assessed. CD8(+) T cell IR was assessed by direct interferon gamma ELISpot analysis. Overall survival and disease-free survival were analyzed by Cox proportional hazard modeling. RESULTS:Out of 332 patients, 57 developed IAE, the majority of which were dermatologic (minimum Common Terminology Criteria for Adverse Events [CTCAE] grade 3). Most nondermatologic IAE were CTCAE grade 1 and 2. Vitiligo developed in 23 patients (7 %). A total of 174 patients (53 %) developed a CD8(+) response. Presence of IAE was significantly associated with development of IR (70 vs. 49 %, p = 0.005) and with disease-free survival (hazard ratio 0.54, p = 0.043). There were no significant associations relating vitiligo or IR alone with clinical outcomes. CONCLUSIONS:IAE are associated with a higher rate of CD8(+) T cell response after vaccination therapy for high-risk melanoma. Our findings suggest either that antitumor activity induced by class I MHC-restricted peptide vaccines may depend on immunologic effects beyond simple expansion of CD8(+) T cells or that the intrinsic inflammatory response of patients contributes to clinical outcome in melanoma.

SUBMITTER: Hu Y

PROVIDER: S-EPMC4192070 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma.

Hu Yinin Y Smolkin Mark E ME White Emily J EJ Petroni Gina R GR Neese Patrice Y PY Slingluff Craig L CL

Annals of surgical oncology 20140520 12

<h4>Background</h4>Multipeptide vaccines for melanoma may cause inflammatory adverse events (IAE). We hypothesize that IAE are associated with a higher rate of immune response (IR) to vaccination and improved clinical outcomes.<h4>Methods</h4>Adult patients with resected, high-risk (stage IIB to IV) melanoma were vaccinated with a combination of 12 class I major histocompatibility complex (MHC)-restricted melanoma epitopes, and IAE were recorded. A separate category for hypopigmentation (vitilig ...[more]

PMID: 24841355

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Project description:BackgroundImmunotherapies and targeted therapies have drastically improved survival in metastatic melanoma, but they can cause a range of adverse events (AEs). Understanding the costs of these events would facilitate an accurate comparison of melanoma treatments.ObjectiveTo compare the costs and frequency of AEs associated with immunotherapy and with targeted therapy in elderly patients with metastatic melanoma.MethodsWe conducted a retrospective cohort study using Medicare claims data from 2011 to 2014. Patients included had to have ≥1 diagnoses of metastatic melanoma and ≥1 claims for an immunotherapy or targeted therapy. We compared the 30-day expenditures of patients with and without each AE using a generalized linear model to determine the incremental cost per AE in patients who received immunotherapy or targeted therapy. The baseline demographic and clinical differences were adjusted for using propensity score with inverse probability of treatment. We also compared the mean costs of AEs associated with immunotherapy and targeted therapy.ResultsA total of 844 patients were included in the study (mean age, 75 years; standard deviation, 14 years). The mean baseline Charlson Comorbidity Index score was 8.4, and 65% of the patients were male. The mean cost for AEs was highest for respiratory events (ie, $24,150). Gastrointestinal, respiratory, and hematologic AEs were more common in patients who received immunotherapy, whereas general and administration-site AEs and other AEs (eg, fatigue, infections, muscular weakness) were more frequent in patients who received targeted therapy. AE-related costs with immunotherapy were highest for gastrointestinal, respiratory, and pain-related AEs; AEs with targeted therapy were highest for cardiovascular and general and administration-site events.ConclusionThese findings suggest that incremental costs associated with treatment-related AEs among elderly patients with metastatic melanoma were substantial, but the risks for and costs of the various types of AEs differed by therapy. Understanding the risks for and costs of AEs associated with the various therapeutic options can inform treatment decision-making in elderly patients with metastatic melanoma.

Project description:INTRODUCTION:Objective response rates (ORR) appear to be higher in melanoma patients who develop immune-related adverse events (irAEs), but whether there is a similar association between irAEs and survival remains unknown. MATERIALS AND METHODS:Patients with advanced melanoma treated with single-agent pembrolizumab or nivolumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAEs that occurred while on anti-programmed cell death protein 1 (PD-1) checkpoint inhibitors. The primary objective was to compare overall survival (OS) with patients who developed any irAEs versus those who did not. Secondary outcomes included progression-free survival (PFS) and ORR. RESULTS:Among 186 patients, any-grade and grade ?3 irAEs occurred in 88 (47%) and 27 (15%) patients, respectively; one patient died of pneumonitis. In a landmark analysis excluding patients who died within the first 12?weeks, the median follow-up was 24 months, 20 months in patients without any irAEs and 26 months in patients with irAEs (p = .006). Median OS was 39 versus 23 months (hazard ratio [HR], 0.46; p = .001) for any irAE and no irAE, respectively, and median OS not reached versus 29 months for grade ?3 irAEs and no grade ?3 irAEs, respectively. In multivariate analysis, elevated lactate dehydrogenase correlated with reduced OS (HR, 2.34; p = .001), whereas each additional cycle of treatment received (HR, 0.94; p <?.001) and development of grade ?3 irAEs (HR, 0.29, p = .024) were significantly associated with longer OS. CONCLUSION:Anti-PD-1-associated grade ?3 irAEs in patients with advanced melanoma is associated with better patient outcomes, including overall survival. IMPLICATIONS FOR PRACTICE:Previous prospective randomized clinical trials demonstrate improved response rates in patients with melanoma who develop select adverse events. The current population-based real-world study in advanced melanoma reports an association with anti-programmed cell death protein 1 (PD-1)-induced grade ?3 immune-related adverse events (irAEs) and better patient outcomes, including overall survival. These results suggest that irAEs may be a manifestation of a patient's ability to mount a systemic immune response from PD-1-directed therapies, which may be associated with therapeutic benefit. The finding of irAEs coinciding with clinical benefit from these therapies supposes that these events are, by and large, unavoidable, and the critical management of irAEs remains essential for optimizing patient outcomes.

Project description:AIM:To study the type and frequency of adverse events associated with anti-tumor necrosis factor (TNF) therapy and evaluate for any serologic and genetic associations. METHODS:This study was a retrospective review of patients attending the inflammatory bowel disease (IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer's protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure. RESULTS:Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients (21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the anti-TNF agent. In total: n = 66 (5%) infusion reactions; n = 49 (4%) allergic/serum sickness reactions; n = 19 (1.5%) lupus-like reactions, n = 52 (4%) rash, n = 18 (1.4%) infections. In Crohn's disease, IgA ASCA (P = 0.04) and IgG-ASCA (P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions (P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT (Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event. CONCLUSION:Our study shows 1 in 5 IBD patients experience an adverse event to anti-TNF therapy with novel serologic, genetic , and pathways associations.

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Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma.

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Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma.

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