394 Interleukin-8–neutralizing monoclonal antibody BMS-986253 plus nivolumab (NIVO) in biomarker-enriched, primarily anti–PD-(L)1–experienced patients with advanced cancer: initial phase 1 results

Davar, Diwakar; Simonelli, Matteo; Gutierrez, Martin; Calvo, Emiliano; Melear, Jason M.; Piha‐Paul, Sarina A.; Richards, Donald A.; Dallos, Matthew C.; Parameswaran, Janaki; Kumar, Vinit; Zhao, Xiaochen; Dutta, Santanu; Melero, Ignacio

doi:10.1136/jitc-2020-sitc2020.0394

Cited by 6 publications

(6 citation statements)

References 3 publications

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“…Because IL8 was previously shown to be expressed in higher levels in patients that progressed from II to stage III melanoma ( 23 ), it is a poor prognostic marker in stage IV melanoma, and a decrease in levels from baseline are correlated with response to anti-PD-1 treatment ( 25 ), an anti-IL8 antibody (HuMax-IL8, BMS-986253) has been developed. In a study (NCT03400332) testing nivolumab + anti-IL8 therapy in patients with increased IL8 serum levels showed dose-proportional pharmacokinetics and reduction in serum IL8 levels, resulting in partial responses ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Hoefsmit

Völlmy

Rozeman

et al. 2023

Cancer Research Communications

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The response rates upon neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma are higher as compared to stage IV disease. Given that successful ICB depends on systemic immune response, we hypothesized that systemic immune suppression might be a mechanism responsible for lower response rates in late-stage disease, and also potentially with disease recurrence in early-stage disease. Plasma and serum samples of cohorts of melanoma patients were analyzed for circulating proteins using mass spectrometry proteomic profiling and Olink proteomic assay. A cohort of paired samples of patients with stage III that progressed to stage IV disease (n=64) was used to identify markers associated with higher tumor burden. Baseline patient samples from the OpACIN-neo study (n=83) and PRADO study (n=49; NCT02977052) were used as two independent cohorts to analyze whether the potential identified markers are also associated with disease recurrence after neoadjuvant ICB therapy. When comparing baseline proteins overlapping between patients with progressive disease and patients with recurrent disease, we found leucine-rich alpha-2-glycoprotein 1 (LRG1) to be associated with worse prognosis. Especially non-responder patients to neoadjuvant ICB (OpACIN-neo) with high LRG1 expression had a poor outcome with an estimated 36-month event-free survival of 14% as compared to 83% for non-responders with a low LRG1 expression (P = 0.014). This finding was validated in an independent cohort (P = 0.0021). LRG1 can be used as a biomarker to identify patients with high risk for disease progression and recurrence, and might be a target to be combined with neoadjuvant ICB.

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Section: Discussionmentioning

confidence: 99%

Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Hoefsmit

Völlmy

Rozeman

et al. 2023

Cancer Research Communications

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“…Elevated tumor and serum IL8 is also associated with resistance to immune‐checkpoint inhibitors 24,25 . Correspondingly, adding an anti‐interleukin (IL)8 neutralizing antibody to nivolumab produced preliminary clinical activity in a small trial of patients with advanced cancers, including 28 patients with melanoma 26 . The IL8 paralog, growth‐regulated alpha protein (GRO‐α, gene name: CXCL1 ), is functionally similar to IL8 and has been shown to drive tumorigenesis and angiogenesis in melanoma 27 …”

Section: Discussionmentioning

confidence: 99%

“…24,25 Correspondingly, adding an anti-interleukin (IL)8 neutralizing antibody to nivolumab produced preliminary clinical activity in a small trial of patients with advanced cancers, including 28 patients with melanoma. 26 The IL8 paralog, growth-regulated alpha protein (GROa, gene name: CXCL1), is functionally similar to IL8 and has been shown to drive tumorigenesis and angiogenesis in melanoma. 27 Perhaps somewhat surprisingly, cell adhesion receptors involved in lymphangiogenesis such as integrin b1 were not Similar to the main analysis, except the Cox models were adjusted for the aforementioned covariates along with ulceration (yes vs. no), and positive SLN biopsy (yes vs. no).…”

Section: Discussionmentioning

confidence: 99%

Association of tumor molecular factors with in‐transit metastasis in primary cutaneous melanoma

2022

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Background In‐transit metastases (ITM) are a form of locoregional relapse representing intralymphatic metastatic spread and occur in approximately 4–9% of patients with melanoma >1 mm Breslow thickness. Our objective was to evaluate a combination of clinicopathologic risk factors and gene expression biomarkers predictive of ITM risk. Methods We used PCR to quantify gene expression in diagnostic biopsy tissue across a prospectively designed archival cohort of 854 consecutive thin and intermediate thickness primary cutaneous melanomas. The outcome of interest was ITM >90 days after a melanoma diagnosis. Cox proportional hazard models were fit to estimate each clinicopathologic and molecular characteristic’s association with the risk of ITM. Results The 5‐year cumulative incidence of ITM was 3.2%. Clinical factors univariately associated with an increased risk of ITM were older age, greater Breslow thickness, greater mitotic rate, lower extremity location, ulceration, and a positive SLN biopsy. Of 108 genes tested, five were significantly upregulated and five significantly downregulated when evaluated in Cox models adjusted for age, Breslow thickness, mitotic rate, and lower extremity location. Among the upregulated genes, the strongest association was observed for interleukin‐8 (IL8). Conclusion A subset of gene expression biomarkers was identified as independently associated with the risk of ITM after adjusting for key covariates. Once sufficiently validated, our results may lead the way to regional therapy trials for a small, selected group of high‐risk patients.

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“…30 An anti-IL-8 antibody (BMS-986253) in combination with ICI has delivered responses in clinical trials of patients with immunotherapy refractory melanoma, including patients with AM. 31 Our group has further identified IL-8 as a mediator of resistance to stereotactic body radiotherapy plus immunotherapy combinations. 32 Leveraging these observations in identifying IL-8 as a mediator of resistance, we have launched a phase I/II study of SBRT with nivolumab and BMS-986253 (NCT04572451) which will investigate the safety and efficacy of this combination to overcome the non-T cell-inflamed TME in melanoma.…”

Section: Open Accessmentioning

confidence: 99%

Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma

Augustin,

Newman,

et al. 2023

J Immunother Cancer

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Acral melanoma (AM) has distinct characteristics as compared with cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICIs). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3+CD8+PD1+intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low versus high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared with responders across cancers, including AM, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.

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394 Interleukin-8–neutralizing monoclonal antibody BMS-986253 plus nivolumab (NIVO) in biomarker-enriched, primarily anti–PD-(L)1–experienced patients with advanced cancer: initial phase 1 results

Cited by 6 publications

References 3 publications

Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Association of tumor molecular factors with in‐transit metastasis in primary cutaneous melanoma

Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma

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