Clinical value of noninvasive biomarkers reflecting a collagen-rich stroma in metastatic melanoma patients treated with anti-PD1 therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3049-3049
Author(s):  
Christina Jensen ◽  
Daan Hurkmans ◽  
Stijn L.W. Koolen ◽  
Morten A. Karsdal ◽  
Ron H.J. Mathijssen ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Poor Response ◽  
Cross Linking ◽  
Survival Outcomes ◽  
Type Iii Collagen ◽  
Collagen Formation ◽  
Type Iii ◽  
Checkpoint Inhibitor Therapy ◽  
Melanoma Patients ◽  
Pre Treatment

3049 Background: Poor response to anti-PD1/PD-L1 remains a clinical challenge in a subgroup of patients with metastatic melanoma. Recent evidence strongly suggests that these poor responses are associated with TGF-β signaling and CD8+ T-cell excluded tumors characterized by a collagen-rich peritumoral stroma that blocks the interaction between T cells and tumor cells. In the pursuit of identifying non-invasive biomarkers associated with a T-cell excluded phenotype and predict resistance/response to immune checkpoint inhibitor therapy, we evaluated the association between blood-based biomarkers measuring type III collagen formation and cross-linking and survival outcomes in metastatic melanoma patients treated with anti-PD1 therapy. Methods: 107 patients with metastatic melanoma who started anti-PD1 monotherapy between May 2016 – March 2019 entered in a prospective real-life study (nivolumab n = 62, pembrolizumab n = 45). Type III collagen formation (PRO-C3) and type III collagen formation and cross-linking (PC3X) were measured with ELISAs in pre-treatment serum. Biomarker levels were associated to Disease Control Rate (according to RECIST v.1.1) by Mann-Whitney test and correlated to survival outcomes by Kaplan-Meier and Cox regression analyses. Results: PRO-C3 was significantly elevated in patients with progressive disease compared to the combined group of patients with complete response, partial response and stable disease (p = 0.046). High PRO-C3 and PC3X ( > 75th percentile) prior to treatment were significantly associated with poor overall survival (PRO-C3: HR = 2.4, p = 0.008; PC3X: HR = 2.2, p = 0.019) and progression free survival (PRO-C3: HR = 1.91, p = 0.016; PC3X: HR = 1.94, p = 0.013). The median overall survival was 417 and 511 days in biomarker high patients compared to 1269 and 1269 days in biomarker low patients, for PRO-C3 and PC3X, respectively. Conclusions: Biomarkers quantified in a pre-treatment liquid biopsy reflecting excessive collagen formation and cross-linking were associated with poor response and survival outcomes in metastatic melanoma patients treated with anti-PD1 therapy. This supports an association between collagen formation and resistance to anti-PD1 therapy. Furthermore, if validated, these non-invasive collagen biomarkers may have potential for guiding patient stratification for immune checkpoint inhibitor therapy and combination therapies. Clinical trial information: NTR7015 .

scholarly journals Identification of an Immature Subset of PMN-MDSC Correlated to Response to Checkpoint Inhibitor Therapy in Patients with Metastatic Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1362
Author(s):  
Françoise Gondois-Rey ◽  
Magali Paul ◽  
Florence Alcaraz ◽  
Sarah Bourass ◽  
Jilliana Monnier ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitor ◽  
T Cell Proliferation ◽  
Low Density ◽  
Direct Cytotoxicity ◽  
Radiological Response ◽  
Checkpoint Inhibitor Therapy ◽  
Pre Treatment ◽  
Immature Cells

PMN-MDSCs support tumor progression and resistance to ICI therapy through their suppressive functions but their heterogeneity limits their use as biomarkers in cancer. Our aim was to investigate the phenotypic and functional subsets of PMN-MDSCs to identify biomarkers of response to ICI therapy. We isolated low-density CD15+ PMNs from patients with metastatic melanoma and assessed their immune-suppressive capacities. Expression of CD10 and CD16 was used to identify mature and immature subsets and correlate them to inhibition of T cell proliferation or direct cytotoxicity. Frequencies of the PMN-MDSCs subsets were next correlated to the radiological response of 36 patients receiving ICI therapy. Mature activated cells constituted the major population of PMN-MDSCs. They were found in a higher proportion in the pre-treatment blood of patients non responders to ICI. A subset of immature cells characterized by intermediate levels of CD10 and CD16, the absence of expression of SIRPα and a strong direct cytotoxicity to T cells was increased in patients responding to ICI. The paradoxical expansion of such cells during ICI therapy suggests a role of PMNs in the inflammatory events associated to efficient ICI therapy and the usefulness of their monitoring in patients care.

scholarly journals P165 Non-invasive biomarkers of type III collagen cross-linking reflects fibrolysis in patient with luminal CROHN’S DISEASE

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S241-S242
Author(s):  
M Pehrsson ◽  
L E Godskesen ◽  
A C Bay-Jensen ◽  
M Asser Karsdal ◽  
A Krag ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Disease Activity ◽  
Collagen Degradation ◽  
Inactive Disease ◽  
Type Iii Collagen ◽  
Collagen Formation ◽  
Type Iii ◽  
Ctx Iii ◽  
Collagen Remodelling ◽  
Active Disease

Abstract Background Type III collagen of the interstitial matrix is highly expressed in fibrotic tissue of Crohn’s disease (CD) and suggested to undergo remodelling during the characteristic deep tissue inflammation. Periods of inflammatory flares and remission could thus be reflected by varying degrees of type III collagen degradation and formation in relation to fibrogenesis and resolution of fibrosis. The aim was to investigate the association between type III collagen remodelling and CD disease phenotypes based on the Montreal classification Methods 40 CD patients were endoscopically assessed according to the Montreal B classification (luminal or stricturing phenotype) and Harvey Bradshaw Index for clinical disease activity (<4 = inactive; >4 = active). Patients were stratified based on both the Montreal B classification and HBI scores. Biomarkers were assessed by ELISA: 1) CTX-III (cross-linked protease degraded fragments of type III collagen), PC3X (cross-linked type III collagen formation), 3) PRO-C3 (type III collagen formation), and 4) C3M (MMP-9 degradation fragments) Results Biomarker levels of CTX-III was significantly elevated in CD patients with luminal- and clinically inactive- disease compared to patients with stricturing- and clinically inactive- disease and luminal- and clinically active- disease (p<0.01 and p<0.05, fig 1A). The levels of net fibrolysis of cross-linked type III collagen (CTX-III/PC3X) was significantly higher in patients with luminal- and clinically inactive- disease compared to patients with stricturing- and clinically inactive- disease (p<0.001), luminal- and clinically active- disease (p<0.001), and patients with stricturing- and clinically active- disease (p<0.05, fig 1C). Significantly elevated levels of net type III collagen degradation (C3M/PRO-C3) were observed in patients with a luminal- and clinically active- disease compared to luminal- and clinically inactive- as well as stricturing- and clinically inactive- disease (p<0.05). Furthermore, net type III collagen degradation was elevated compared to patients with stricturing- and clinically active- disease (p<0.05, fig 1F). Biomarker levels of PC3X, C3M, and PRO-C3 were unable to differentiate between patient groupings (fig 1B, D, and E) Conclusion Proteolytic degradation of cross-linked type III collagen (CTX-III) reflecting resolution of fibrosis in CD patients with luminal disease, may be associated with a protective effect against fibrogenesis and progression to fibrostenosis. These data indicate differences in cross-linked and non-cross-linked type III collagen remodelling in CD patients, and their potential use for differentiating patient phenotypes and disease activity

scholarly journals Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma

2020 ◽  
Vol 8 (2) ◽  
pp. e001193
Author(s):  
Daan P Hurkmans ◽  
Christina Jensen ◽  
Stijn L W Koolen ◽  
Joachim Aerts ◽  
Morten Asser Karsdal ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Clinical Outcome ◽  
Metastatic Melanoma ◽  
Type Iv Collagen ◽  
Type Iii Collagen ◽  
Cox Regression Analysis ◽  
High Baseline ◽  
Type Iii ◽  
Type Iv ◽  
M1 Macrophage

BackgroundImmune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) receptor induce a response in only a subgroup of patients with metastatic melanoma. Previous research suggests that transforming growth factor beta signaling and a collagen-rich peritumoral stroma (tumor fibrosis), may negatively interfere with the interaction between T cells and tumor cells and thereby contribute to resistance mechanisms by immune-exclusion, while increased tumor infiltration of M1-like macrophages enhances T cell activity. Hence, the current study aimed to assess the relationship between blood-based markers of collagen or vimentin turnover (reflecting M1 macrophage activity) and clinical outcome in patients with metastatic melanoma after PD-1 inhibition.MethodsPatients with metastatic melanoma who were treated with anti-PD-1 monotherapy between May 2016 and March 2019 were included in a prospective observational study. N-terminal pro-peptide of type III collagen (PRO-C3) cross-linked N-terminal pro-peptides of type III collagen (PC3X), matrix metalloprotease (MMP)-degraded type III (C3M) and type IV collagen (C4M), granzyme B-degraded type IV collagen and citrullinated and MMP-degraded vimentin (VICM) were measured with immunoassays in serum before (n=107), and 6 weeks after the first administration of immunotherapy (n=94). The association between biomarker levels and overall survival (OS) or progression-free survival (PFS) was assessed.ResultsMultivariate Cox regression analysis identified high baseline PRO-C3 (Q4) and PC3X (Q4) as independent variables of worse PFS (PRO-C3: HR=1.81, 95% CI=1.06 to 3.10, p=0.030 and PC3X: HR=1.86, 95% CI=1.09 to 3.18, p=0.023). High baseline PRO-C3 was also independently related to worse OS (HR=2.08, 95% CI=1.06 to 4.09, p=0.035), whereas a high C3M/PRO-C3 ratio was related to improved OS (HR=0.42, 95% CI=0.20 to 0.90, p=0.025). An increase in VICM (p<0.0001; in 56% of the patients) was observed after 6 weeks of treatment, and an increase in VICM was independently associated with improved OS (HR=0.28, 95% CI=0.10 to 0.77, p=0.014).ConclusionsBlood-based biomarkers reflecting excessive type III collagen turnover were associated with worse OS and PFS after PD-1 inhibition in metastatic melanoma. Moreover, an increase in VICM levels after 6 weeks of treatment was associated with improved OS. These findings suggest that type III collagen and vimentin turnover contribute to resistance/response mechanisms of PD-1 inhibitors and hold promise of assessing extracellular matrix-derived and stroma-derived components to predict immunotherapy response.

Isolation and Structure of the Amino-Terminal Cross-linking Region in Insoluble Type III Collagen

1976 ◽  
Vol 357 (2) ◽  
pp. 1409-1416 ◽  
Author(s):  
Udo BECKER ◽  
Peter P. FIETZEK ◽  
Hans NOWACK ◽  
Rupert TIMPL
Keyword(s):  
Cross Linking ◽  
Type Iii Collagen ◽  
Type Iii ◽  
Amino Terminal

Aldehyde content and cross-linking of type III collagen

1976 ◽  
Vol 69 (1) ◽  
pp. 128-134 ◽  
Author(s):  
Katsuyuki Fujii ◽  
Marvin L. Tanzer ◽  
Bette V. Nusgens ◽  
Charles M. Lapiere
Keyword(s):  
Cross Linking ◽  
Type Iii Collagen ◽  
Type Iii ◽  
Aldehyde Content

Autoantibodies as predictors for survival and immune-related adverse events in checkpoint inhibition therapy of metastasized melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10011-10011 ◽  
Author(s):  
Jessica Cecile Hassel ◽  
Hans-Dieter Zucht ◽  
Joanna Mangana ◽  
Reinhard Dummer ◽  
Claudia Pföhler ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
B Cell ◽  
Metastatic Melanoma ◽  
Cell Response ◽  
Statistical Tests ◽  
Cox Regression Analysis ◽  
Melanoma Patients ◽  
Pre Treatment ◽  
B Cell Response

10011 Background: Increasing evidence suggests that the B cell response in cancer patients is an important component of anti-tumour immunity. Autoantibodies targeting tumour and self-antigens may serve as biomarkers of anti-tumour and auto-immunity. As they can be measured in patient' sera, they have great potential as clinical routine biomarkers. The objective of this study was to explore if autoantibodies are associated with survival and immune related adverse events (irAE) in patients with metastatic melanoma under checkpoint inhitibor (CPI) therapy. Methods: Pre-treatment serum samples from 333 metastatic melanoma patients receiving CPI therapy at 5 European centers were retrospectively used to identify autoantibody signatures for survival and irAE. We designed a cancer immunotherapy antigen array comprising 832 autoimmune and tumour antigens as well as immune and cancer pathway proteins. Statistical tests were separately performed for patients treated with anti-CTLA4 (alone or in combination) and with anti-PD1 antibody monotherapy. Cox-regression analysis and univariate statistical tests were applied for biomarker discovery. Progression free and overall survival was measured from treatment initiation to tumor progression or death date. irAE were recorded including onset date and grade (CTC-AE). Results: For each therapy group we identified a set of autoantibody reactivities in untreated melanoma patients that were associated with the development of irAEs and/or survival. The identified autoantibodies target a diverse set of antigens comprising neoantigens (p53), cancer testis antigens (MAGEB4), paraneoplastic antigens (gephyrin), autoantigens (ribosomal proteins, Nor-90) and FGFR1. Autoantigens that correlated with irAE and survival were e.g. anti-MAGEB4 and anti-FGFR1. Elevated anti-MAGEB4 pre-treatment levels were associated with longer overall survival (p = 0.002, HR = 0.77) and the development of irAEs (p = 0.002, HR = 1.27) in ipilimumab +/- nivolumab treated patients. Higher pre-treatment anti-FGFR1 antibodies were associated with shorter survival (p = 0.008, HR = 1.27) and a lower a lower frequency of irAEs (p = 0.04, HR = 0.69) in these patients. Conclusions: We identified autoantibody targets suggesting a diverse B cell response to antigens expressed in tumours and those associated with autoimmunity. Depending on the specific antigen, the immune response towards those antigens may be associated with anti-tumour or pro-tumour responses.

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