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Kinase Insert Domain Receptor Q472H Pathogenic Germline Variant Impacts Melanoma Tumor Growth and Patient Treatment Outcomes

Ibrahim, Milad; Illa-Bochaca, Irineu; Fa"™ak, Faisal; Monson, Kelsey R.; Ferguson, Robert; Lyu, Chen; Vega-Saenz de Miera, Eleazar; Johannet, Paul; Chou, Margaret; Mastroianni, Justin; Darvishian, Farbod; Kirchhoff, Tomas; Zhong, Judy; Krogsgaard, Michelle; Osman, Iman
Background: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy. Methods: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi. Results: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic (p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi (p = 0.022) and a trend with worse PFS to anti-PD1 therapy (p = 0.06). KDR-Var B16 murine models had increased average tumor volume (p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes (p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors (p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib. Conclusions: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials.
ISSN: 2072-6694
CID: 5629852

Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-Risk Resected Melanoma

Goodman, Rachel S; Lawless, Aleigha; Woodford, Rachel; Fa'ak, Faisal; Tipirneni, Asha; Patrinely, J Randall; Yeoh, Hui Ling; Rapisuwon, Suthee; Haydon, Andrew; Osman, Iman; Mehnert, Janice M; Long, Georgina V; Sullivan, Ryan J; Carlino, Matteo S; Menzies, Alexander M; Johnson, Douglas B
IMPORTANCE:Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. OBJECTIVE:To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti-PD-1 therapy. DESIGN, SETTING, AND PARTICIPANTS:This retrospective multicenter cohort study analyzed patients treated with adjuvant anti-PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation (range, 18.2 to 70.4 months). MAIN OUTCOMES AND MEASURES:Incidence, spectrum, and ultimate resolution vs persistence of chronic irAEs (defined as those persisting at least 3 months after therapy cessation). Descriptive statistics were used to analyze categorical and continuous variables. Kaplan-Meier curves assessed survival, and Wilson score intervals were used to calculate CIs for proportions. RESULTS:Among 318 patients, 190 (59.7%) were male (median [IQR] age, 61 [52.3-72.0] years), 270 (84.9%) had a cutaneous primary, and 237 (74.5%) were stage IIIB or IIIC at presentation. Additionally, 226 patients (63.7%) developed acute irAEs arising during treatment, including 44 (13.8%) with grade 3 to 5 irAEs. Chronic irAEs, persisting at least 3 months after therapy cessation, developed in 147 patients (46.2%; 95% CI, 0.41-0.52), of which 74 (50.3%) were grade 2 or more, 6 (4.1%) were grade 3 to 5, and 100 (68.0%) were symptomatic. With long-term follow-up (median [IQR], 1057 [915-1321] days), 54 patients (36.7%) experienced resolution of chronic irAEs (median [IQR] time to resolution of 19.7 [14.4-31.5] months from anti-PD-1 start and 11.2 [8.1-20.7] months from anti-PD-1 cessation). Among patients with persistent irAEs present at last follow-up (93 [29.2%] of original cohort; 95% CI, 0.25-0.34); 55 (59.1%) were grade 2 or more; 41 (44.1%) were symptomatic; 24 (25.8%) were using therapeutic systemic steroids (16 [67%] of whom were on replacement steroids for hypophysitis (8 [50.0%]) and adrenal insufficiency (8 [50.0%]), and 42 (45.2%) were using other management. Among the 54 patients, the most common persistent chronic irAEs were hypothyroid (38 [70.4%]), arthritis (18 [33.3%]), dermatitis (9 [16.7%]), and adrenal insufficiency (8 [14.8%]). Furthermore, 54 [17.0%] patients experienced persistent endocrinopathies, 48 (15.1%) experienced nonendocrinopathies, and 9 (2.8%) experienced both. Of 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) experienced no effect on chronic irAEs whereas 12 (32.4%) experienced a flare in their chronic toxicity. Twenty patients (54.1%) experienced a distinct irAE. CONCLUSIONS AND RELEVANCE:In this cohort study of 318 patients who received adjuvant anti-PD-1, chronic irAEs were common, affected diverse organ systems, and often persisted with long-term follow-up requiring steroids and additional management. These findings highlight the likelihood of persistent toxic effects when considering adjuvant therapies and need for long-term monitoring and management.
PMID: 37535354
ISSN: 2574-3805
CID: 5594612

Germline immunomodulatory expression quantitative trait loci (ieQTLs) associated with immune-related toxicity from checkpoint inhibition

Ferguson, Robert; Chat, Vylyny; Morales, Leah; Simpson, Danny; Monson, Kelsey R; Cohen, Elisheva; Zusin, Sarah; Madonna, Gabriele; Capone, Mariaelena; Simeone, Ester; Pavlick, Anna; Luke, Jason J; Gajewski, Thomas F; Osman, Iman; Ascierto, Paolo; Weber, Jeffrey; Kirchhoff, Tomas
BACKGROUND:Immune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients; however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored whether germline genetic variants controlling the expression of 42 immunomodulatory genes were associated with the risk of irAEs in melanoma patients treated with the single-agent anti-CTLA-4 antibody ipilimumab (IPI). METHODS:We identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped in IPI-treated melanoma patients, collected as part of a multi-institutional collaboration. We tested the association of ieQTLs with irAEs in a discovery cohort of 95 patients, followed by validation in an additional 97 patients. RESULTS:We found that the alternate allele of rs7036417, a variant linked to increased expression of SYK, was strongly associated with an increased risk of grade 3-4 toxicity [odds ratio (OR) = 7.46; 95% confidence interval (CI) = 2.65-21.03; p = 1.43E-04]. This variant was not associated with response (OR = 0.90; 95% CI = 0.37-2.21; p = 0.82). CONCLUSION/CONCLUSIONS:We report that rs7036417 is associated with increased risk of severe irAEs, independent of IPI efficacy. SYK plays an important role in B-cell/T-cell expansion, and increased pSYK has been reported in patients with autoimmune disease. The association between rs7036417 and IPI irAEs in our data suggests a role of SYK overexpression in irAE development. These findings support the hypothesis that inherited variation in immune-related pathways modulates ICI toxicity and suggests SYK as a possible future target for therapies to reduce irAEs.
PMID: 37301715
ISSN: 1879-0852
CID: 5535092

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 1st-3rd, 2022-Naples, Italy)

Ascierto, Paolo A; Agarwala, Sanjiv S; Warner, Allison Betof; Ernstoff, Marc S; Fox, Bernard A; Gajewski, Thomas F; Galon, Jérôme; Garbe, Claus; Gastman, Brian R; Gershenwald, Jeffrey E; Kalinski, Pawel; Krogsgaard, Michelle; Leidner, Rom S; Lo, Roger S; Menzies, Alexander M; Michielin, Olivier; Poulikakos, Poulikos I; Weber, Jeffrey S; Caracò, Corrado; Osman, Iman; Puzanov, Igor; Thurin, Magdalena
Outcomes for patients with melanoma have improved over the past decade with the clinical development and approval of immunotherapies targeting immune checkpoint receptors such as programmed death-1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte antigen-4 (CTLA-4). Combinations of these checkpoint therapies with other agents are now being explored to improve outcomes and enhance benefit-risk profiles of treatment. Alternative inhibitory receptors have been identified that may be targeted for anti-tumor immune therapy, such as lymphocyte-activation gene-3 (LAG-3), as have several potential target oncogenes for molecularly targeted therapy, such as tyrosine kinase inhibitors. Unfortunately, many patients still progress and acquire resistance to immunotherapy and molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been shown to improve prognosis compared to monotherapy. The number of new combinations treatment under development for melanoma provides options for the number of patients to achieve a therapeutic benefit. Many diagnostic and prognostic assays have begun to show clinical applicability providing additional tools to optimize and individualize treatments. However, the question on the optimal algorithm of first- and later-line therapies and the search for biomarkers to guide these decisions are still under investigation. This year, the Melanoma Bridge Congress (Dec 1st-3rd, 2022, Naples, Italy) addressed the latest advances in melanoma research, focusing on themes of paramount importance for melanoma prevention, diagnosis and treatment. This included sessions dedicated to systems biology on immunotherapy, immunogenicity and gene expression profiling, biomarkers, and combination treatment strategies.
PMID: 37507765
ISSN: 1479-5876
CID: 5594222

Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events

Fa'ak, Faisal; Buni, Maryam; Falohun, Adewunmi; Lu, Huifang; Song, Juhee; Johnson, Daniel H; Zobniw, Chrystia M; Trinh, Van A; Awiwi, Muhammad Osama; Tahon, Nourel Hoda; Elsayes, Khaled M; Ludford, Kaysia; Montazari, Emma J; Chernis, Julia; Dimitrova, Maya; Sandigursky, Sabina; Sparks, Jeffrey A; Abu-Shawer, Osama; Rahma, Osama; Thanarajasingam, Uma; Zeman, Ashley M; Talukder, Rafee; Singh, Namrata; Chung, Sarah H; Grivas, Petros; Daher, May; Abudayyeh, Ala; Osman, Iman; Weber, Jeffrey; Tayar, Jean H; Suarez-Almazor, Maria E; Abdel-Wahab, Noha; Diab, Adi
BACKGROUND:Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs. METHODS:We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment. RESULTS:We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04). CONCLUSION/CONCLUSIONS:Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749).
PMID: 37328287
ISSN: 2051-1426
CID: 5538402

The "Great Debate" at Melanoma Bridge 2022, Naples, December 1st-3rd, 2022

Ascierto, Paolo A; Blank, Christian; Eggermont, Alexander M; Garbe, Claus; Gershenwald, Jeffrey E; Hamid, Omid; Hauschild, Axel; Luke, Jason J; Mehnert, Janice M; Sosman, Jeffrey A; Tawbi, Hussein A; Mandalà, Mario; Testori, Alessandro; Caracò, Corrado; Osman, Iman; Puzanov, Igor
The Great Debate session at the 2022 Melanoma Bridge congress (December 1-3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate.
PMID: 37072748
ISSN: 1479-5876
CID: 5464432

An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma

Davalos, Veronica; Lovell, Claudia D; Von Itter, Richard; Dolgalev, Igor; Agrawal, Praveen; Baptiste, Gillian; Kahler, David J; Sokolova, Elena; Moran, Sebastian; Piqué, Laia; Vega-Saenz de Miera, Eleazar; Fontanals-Cirera, Barbara; Karz, Alcida; Tsirigos, Aristotelis; Yun, Chi; Darvishian, Farbod; Etchevers, Heather C; Osman, Iman; Esteller, Manel; Schober, Markus; Hernando, Eva
Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to-mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 - isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanoma progression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
PMID: 37015919
ISSN: 2041-1723
CID: 5463692

Correction: Tumor immunogenomic signatures improve a prognostic model of melanoma survival

Morales, Leah; Simpson, Danny; Ferguson, Robert; Cadley, John; Esteva, Eduardo; Monson, Kelsey; Chat, Vylyny; Martinez, Carlos; Weber, Jefrey; Osman, Iman; Kirchhof, Tomas
PMID: 37004035
ISSN: 1479-5876
CID: 5463542

Genomic and transcriptomic analyses of NF1-mutant melanoma identify potential targeted approach for treatment

Jour, George; Illa-Bochaca, Irineu; Ibrahim, Milad; Donnelly, Douglas; Zhu, Kelsey; Vega-Saenz de Miera, Eleazar; Vasudevaraja, Varshini; Mezzano, Valeria; Ramswami, Sitharam; Yeh, Yu-Hsin; Winskill, Carolyn; Betensky, Rebecca A; Mehnert, Janice; Osman, Iman
There is currently no targeted therapy to treat NF1-mutant melanomas. Herein, we compared the genomic and transcriptomic signatures of NF1-mutant and NF1-WT melanoma to reveal potential treatment targets for this subset of patients. Genomic alterations were verified using qPCR, and differentially expressed genes were independently validated using TCGA data, and immunohistochemistry (IHC). Digital spatial profiling (DSP) with multiplex IHC and immunofluorescence (IF) were used to validate the signatures. The efficacy of combinational regimens driven by these signatures was tested through in vitro assays using low-passage cell lines. Pathogenic NF1 mutations were identified in 27% cases. NF1-mutant melanoma expressed higher proliferative markers MK167 and CDC20 compared to NF1-WT (P=0.008), which was independently validated both in the TCGA dataset (P=0.01, P=0.03) and with IHC (P=0.013, P=0.036), respectively. DSP analysis showed upregulation of LY6E within the tumor cells [FDR<0.01, lg2FC>1], confirmed with multiplex IF showing co-localization of LY6E in melanoma cells. The combination of MEK and CDC20 co-inhibition induced both cytotoxic and cytostatic effects, decreasing CDC20 expression in multiple NF1-MUT cell lines. In conclusion, NF1-mutant melanoma is associated with a distinct genomic and transcriptomic profile. Our data support investigating CDC20 inhibition with MAPK pathway inhibitors as a targeted regimen in this melanoma subtype.
PMID: 35988589
ISSN: 1523-1747
CID: 5338052

A genome-wide association study of germline variation and melanoma prognosis

Chat, Vylyny; Dagayev, Sasha; Moran, Una; Snuderl, Matija; Weber, Jeffrey; Ferguson, Robert; Osman, Iman; Kirchhoff, Tomas
Background: The high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers. Methods: We performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naïve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression. Results: We found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05"“4.81), p=1.48×10-7; and rs77480547 in SH3BP4: HR=3.02 (2.02"“4.52), p=7.58×10-8, both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone. Conclusions: Our study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma.
ISSN: 2234-943x
CID: 5424662