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Preexisting immune-mediated inflammatory disease is associated with improved survival and increased toxicity in melanoma patients who receive immune checkpoint inhibitors

Gulati, Nicholas; Celen, Arda; Johannet, Paul; Mehnert, Janice M; Weber, Jeffrey; Krogsgaard, Michelle; Osman, Iman; Zhong, Judy
BACKGROUND:Immune-related adverse events (irAEs) are common, clinically significant autoinflammatory toxicities observed with immune checkpoint inhibitors (ICI). Preexisting immune-mediated inflammatory disease (pre-IMID) is considered a relative contraindication to ICI due to the risk of inciting flares. Improved understanding of the risks and benefits of treating pre-IMID patients with ICI is needed. METHODS:We studied melanoma patients treated with ICI and enrolled in a prospective clinicopathological database. We compiled a list of 23 immune-mediated inflammatory diseases and evaluated their presence prior to ICI. We tested the associations between pre-IMID and progression-free survival (PFS), overall survival (OS), and irAEs. RESULTS:In total, 483 melanoma patients were included in the study; 74 had pre-IMID and 409 did not. In patients receiving ICI as a standard of care (SoC), pre-IMID was significantly associated with irAEs (p = 0.04) as well as improved PFS (p = 0.024) and OS (p = 0.007). There was no significant association between pre-IMID and irAEs (p = 0.54), PFS (p = 0.197), or OS (p = 0.746) in patients treated through a clinical trial. Pre-IMID was significantly associated with improved OS in females (p = 0.012), but not in males (p = 0.35). CONCLUSIONS:The dichotomy of the impact of pre-IMID on survival and irAEs in SoC versus clinical trial patients may reflect the inherit selection bias in patients accrued in clinical trials. Future mechanistic work is required to better understand the differences in outcomes between female and male pre-IMID patients. Our data challenge the notion that clinicians should avoid ICI in pre-IMID patients, although close monitoring and prospective clinical trials evaluating ICI in this population are warranted.
PMCID:8559502
PMID: 34647433
ISSN: 2045-7634
CID: 5062002

Targeting the Atf7ip-Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity

Hu, Hai; Khodadadi-Jamayran, Alireza; Dolgalev, Igor; Cho, Hyunwoo; Badri, Sana; Chiriboga, Luis A; Zeck, Briana; Lopez De Rodas Gregorio, Miguel; Dowling, Catríona M; Labbe, Kristen; Deng, Jiehui; Chen, Ting; Zhang, Hua; Zappile, Paul; Chen, Ze; Ueberheide, Beatrix; Karatza, Angeliki; Han, Han; Ranieri, Michela; Tang, Sittinon; Jour, George; Osman, Iman; Sucker, Antje; Schadendorf, Dirk; Tsirigos, Aristotelis; Schalper, Kurt A; Velcheti, Vamsidhar; Huang, Hsin-Yi; Jin, Yujuan; Ji, Hongbin; Poirier, John T; Li, Fei; Wong, Kwok-Kin
Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7-interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.
PMID: 34462284
ISSN: 2326-6074
CID: 5061142

Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma

Usyk, Mykhaylo; Pandey, Abhishek; Hayes, Richard B; Moran, Una; Pavlick, Anna; Osman, Iman; Weber, Jeffrey S; Ahn, Jiyoung
BACKGROUND:Immune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; however, not all patients respond to this treatment and many develop potentially life-threatening immune-related adverse events (irAEs). Identifying individuals who will develop irAEs is critical in order to improve the quality of care. Here, we prospectively demonstrate that the gut microbiome predicts irAEs in melanoma patients undergoing ICB. METHODS:Pre-, during, and post-treatment stool samples were collected from 27 patients with advanced stage melanoma treated with IPI (anti-CTLA-4) and NIVO (anti-PD1) ICB inhibitors at NYU Langone Health. We completed 16S rRNA gene amplicon sequencing, DNA deep shotgun metagenomic, and RNA-seq metatranscriptomic sequencing. The divisive amplicon denoising algorithm (DADA2) was used to process 16S data. Taxonomy for shotgun sequencing data was assigned using MetaPhlAn2, and gene pathways were assigned using HUMAnN 2.0. Compositionally aware differential expression analysis was performed using ANCOM. The Cox-proportional hazard model was used to assess the prospective role of the gut microbiome (GMB) in irAES, with adjustment for age, sex, BMI, immune ICB treatment type, and sequencing batch. RESULTS:= 0.88, p < 0.001). CONCLUSIONS:We identified two distinct fecal bacterial community clusters which are associated differentially with irAEs in ICB-treated advanced melanoma patients.
PMCID:8513370
PMID: 34641962
ISSN: 1756-994x
CID: 5046112

Clinical outcomes in cancer patients with COVID-19

Sawyers, Amelia; Chou, Margaret; Johannet, Paul; Gulati, Nicholas; Qian, Yingzhi; Zhong, Judy; Osman, Iman
BACKGROUND:Early reports on cancer patients with coronavirus disease 2019 (COVID-19) corroborated speculation that cancer patients are at increased risk for becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developing severe COVID-19. However, cancer patients are a heterogeneous population and their corresponding risk may be different. AIM/OBJECTIVE:To compare COVID-19 presentation in patients with active malignancy to those with a history of cancer to determine the impact of cancer status on COVID-19 outcomes in the two groups. METHODS AND RESULTS/RESULTS:Of the 6724 patients who were hospitalized at NYU Langone Health (3/16/20-7/31/20) and tested positive for SARS-CoV-2, 580 had either active cancer (n = 221) or a history of cancer (n = 359). We compared the baseline clinicodemographic characteristics and hospital courses of the two groups. We studied the relationship between cancer status and the rate of admission to the intensive care unit (ICU), use of invasive mechanical ventilation (IMV), and all-cause mortality. The two groups had similar laboratory results associated with COVID-19 infection, incidence of venous thromboembolism, and incidence of severe COVID-19. Active cancer status was not associated with the rate of ICU admission (p = .307) or use of IMV (p = .236), but was significantly associated with worse all-cause mortality in both univariate and multivariate analysis with odds ratios of 1.48 (95% confidence interval [CI]: 1.04-2.09; p = .028) and 1.71 (95% CI: 1.12-2.63; p = .014), respectively. CONCLUSION/CONCLUSIONS:Active cancer patients had worse survival outcomes compared to patients with a history of cancer despite similar COVID-19 disease characteristics in the two groups. Our data suggest that cancer care should continue with minimal interruptions during the pandemic to bring about response and remission as soon as possible.
PMCID:8420395
PMID: 34409775
ISSN: 2573-8348
CID: 5066872

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 3rd-5th, 2020, Italy)

Ascierto, Paolo A; Blank, Christian; Dummer, Reinhard; Ernstoff, Marc S; Ferrone, Soldano; Fox, Bernard A; Gajewski, Thomas F; Garbe, Claus; Hwu, Patrick; Kalinski, Pawel; Krogsgaard, Michelle; Lo, Roger S; Luke, Jason J; Neyns, Bart; Postow, Michael A; Quezada, Sergio A; Teng, Michele W L; Trinchieri, Giorgio; Testori, Alessandro; Caracò, Corrado; Osman, Iman; Puzanov, Igor; Thurin, Magdalena
Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers but they have yet to be fully characterized and implemented clinically. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd-5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.
PMCID:8243582
PMID: 34193182
ISSN: 1479-5876
CID: 4965022

Impact of molecular testing in advanced melanoma on outcomes in a tertiary cancer center and as reported in a publicly available database

Dimitrova, Maya; Kim, Min Jae; Osman, Iman; Jour, George
BACKGROUND:In patients with advanced melanoma (MM), genomic profiling may guide treatment decisions in the frontline setting and beyond as specific tumor mutations can be treated with targeted therapy (TT). The range of panel sizes used to identify targetable mutations (TM) can range from a few dozen to whole exome sequencing (WES). AIM/OBJECTIVE:We investigated the impact of panel size and mutation status on first-line treatment selection and outcomes in MM. METHODS AND RESULTS/RESULTS:We analyzed data for 1109 MM patients from three cohorts: 169 patients at NYULH and profiled with the 50 gene Ion Torrent panel (IT), 195 patients at MSKCC, profiled with the 400-gene MSK-IMPACT panel (MSK-I) and 745 patients at seven different sites profiled with WES. Data for cohorts 2 and 3 were extrapolated from the publicly available cBioPortal. Treatment information was available for 100%, 25%, and 0% of patients in cohort 1, 2, and 3, respectively. BRAF and NRAS were among the top five most commonly mutated genes in the IT and MSK-I, whereas for WES only BRAF was a top five mutation. There was no significant difference in OS for BRAF MUT patients treated with immune checkpoint inhibitors (ICI) vs TT in cohort 1 (P = .19), nor for BRAF MUT patients from cohort 1 treated with ICI vs those from cohort 2 treated with TT (P = .762). CONCLUSION/CONCLUSIONS:Public datasets provide population-level data; however, the heterogeneity of reported clinical information limits their value and calls for data standardization. Without evidence of clear clinical benefit of a larger panel size, there is a rationale for adopting smaller, more cost effective panels in MM.
PMID: 34109763
ISSN: 2573-8348
CID: 4900152

Correction to: The urgency of utilizing COVID-19 biospecimens for research in the heart of the global pandemic

Osman, Iman; Cotzia, Paolo; Moran, Una; Donnelly, Douglas; Arguelles-Grande, Carolina; Mendoza, Sandra; Moreira, Andre
PMID: 34082754
ISSN: 1479-5876
CID: 4891972

The ongoing racial disparities in melanoma: An analysis of the Surveillance, Epidemiology, and End Results database (1975-2016)

Qian, Yingzhi; Johannet, Paul; Sawyers, Amelia; Yu, Jaehong; Osman, Iman; Zhong, Judy
BACKGROUND:Although most patients with cutaneous melanoma are non-Hispanic whites (NHWs), minorities consistently suffer worse melanoma-specific survival (MSS). Much of the literature comes from analyses of registries from the 1990s and 2000s. OBJECTIVE:We sought to evaluate whether and to what degree racial disparity in MSS persists since 2010. METHODS:We analyzed 381,035 patients from the Surveillance, Epidemiology, and End Results registry. Race categories included Hispanic, NHW, non-Hispanic black (NHB), non-Hispanic Asian or Pacific Islander (NHAPI), and non-Hispanic American Indian/Alaska Native (NHAIAN). We evaluated the association between MSS and race in 3 time periods: before the year 2000, 2000 to 2009, and 2010 or later. NHW was the reference group for all analyses. RESULTS:Racial disparity worsened from before the year 2000 to 2010 or later for Hispanic (P < .001), NHB (P = .024), and NHAPI (P < .001) patients. Across all minority groups, patients with localized disease suffered increasing disparity (P = .010 for Hispanic, P < .001 for NHB, P = .023 for NHAPI, and P = .042 for NHAIAN patients). Among those with regional and distant disease, Hispanic patients were the only minority to experience worsening disparity (P = .001 and P = .019, respectively). LIMITATIONS/CONCLUSIONS:Lack of immunotherapy and targeted treatment information. CONCLUSIONS:Racial disparity in MSS is worsening. Improving postdiagnosis management for minorities with localized disease is imperative to mitigate disparity and improve survival.
PMID: 32861710
ISSN: 1097-6787
CID: 4770622

Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma

Patrinely, J Randall; Johnson, Rebecca; Lawless, Aleigha R; Bhave, Prachi; Sawyers, Amelia; Dimitrova, Maya; Yeoh, Hui Ling; Palmeri, Marisa; Ye, Fei; Fan, Run; Davis, Elizabeth J; Rapisuwon, Suthee; Long, Georgina V; Haydon, Andrew; Osman, Iman; Mehnert, Janice M; Carlino, Matteo S; Sullivan, Ryan J; Menzies, Alexander M; Johnson, Douglas B
Importance/UNASSIGNED:Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective/UNASSIGNED:To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants/UNASSIGNED:This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures/UNASSIGNED:Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results/UNASSIGNED:Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance/UNASSIGNED:In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.
PMID: 33764387
ISSN: 2374-2445
CID: 4822812

The "Great Debate" at Melanoma Bridge 2020: December, 5th, 2020

Ascierto, Paolo A; Atkins, Michael B; Eggermont, Alexander M; Gershenwald, Jeffrey E; Grob, Jean-Jacques; Hamid, Omid; Sondak, Vernon K; Sosman, Jeffrey A; Tawbi, Hussein A; Weber, Jeffrey S; Caracò, Corrado; Osman, Iman; Puzanov, Igor
The Great Debate session at the 2020 Melanoma Bridge virtual congress (December 3rd-5th, Italy) featured counterpoint views from experts on five specific controversial issues in melanoma. The debates considered whether or not innate immunity is important in the response to cancer and immunotherapy, how useful are the revised American Joint Committee on Cancer (AJCC) classification for the staging of patients, the use of sentinel node biopsy for staging patients, the use of triplet combination of targeted therapy plus immunotherapy versus combined immunotherapy, and the respective benefits of neoadjuvant versus adjuvant therapy. As is usual with Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their own personal opinion.
PMCID:8028182
PMID: 33827575
ISSN: 1479-5876
CID: 4862432