{
  "abstract": "Background Biliary tract cancer (BTC) has a dismal prognosis with a 5-year survival rate of only 10% and limited treatment options for recurrent or metastatic disease. 1 While recent studies have shown that immune checkpoint inhibitors (ICIs) combined with chemotherapy as first-line therapy for BTC is superior to chemotherapy alone, most patients still do not benefit from treatment.2 This highlights an urgent need for better understanding of ICI therapy resistance and development of biomarkers to improve patient selection. When cytotoxic T cells invade from the blood into tissue, granzyme B is released to break down type IV collagen and allow passage through the basement membrane. This process leaves quantifiable fragments of granzyme B degraded type IV collagen in the blood upon cytotoxic T cell invasion.3 In this study, we investigated the pharmacodynamic and predictive potentials of serologically assessed granzyme B degraded type IV collagen (C4G) and release of latent TGF-β (TGF-β LAP) in patients with metastatic BTC receiving radiotherapy and ICI.Methods C4G and TGF-β LAP were measured using competitive ELISA in serum from 61 patients with treatment-refractory, metastatic BTC enrolled in the CheckPAC and CHOCA studies ( NCT02866383, NCT05184400).4Patients were treated with stereotactic body radiotherapy (SBRT) with nivolumab (n = 19) or nivolumab/ipilimumab (n = 42). Samples were obtained prior to the first (baseline) and second cycles of treatment, and at the end of treatment. Biomarker longitudinal changes were assessed for pharmacodynamic effects across treatment types and predictive potential relative to RECIST 1.1. Kaplan-Meier and Cox regression were used to evaluate overall survival (OS); Fisher’s exact test assessed treatment response and pharmacodynamic changes.Results High baseline TGF-β LAP was significantly associated with short OS (HR=2.52, 95% CI 1.34-4.73, p=0.004). Baseline C4G levels were not associated with response (p=0.154) or survival (p=0.44). However, longitudinal changes in C4G were significantly associated with nivolumab/ipilimumab treatment (p=0.001) and increased C4G levels at end of treatment were significantly associated with treatment response (p=0.029), suggesting pharmacodynamic changes in patients receiving nivolumab/ipilimumab and increased T cell priming in responders ( figure 1). A trend towards longer OS was observed with increased C4G levels (HR=0.45, 95% C.I. 0.18-1.13, p=0.09).Conclusions Changes in collagen-derived immune biomarkers detected in blood during treatment were linked to pharmacodynamic changes and treatment response in patients with BTC receiving immunotherapy and radiotherapy. Serological tumor microenvironment markers may help monitor treatment efficacy and guide future clinical decision-making in patients with BTC.References Everhart JE, Ruhl CE. Burden of Digestive Diseases in the United States Part III: Liver, Biliary Tract, and Pancreas. Gastroenterology. 2009 Apr 1;136(4):1134–44.Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2023 Jun 3;401(10391):1853–65.Jensen C, Sinkeviciute D, Madsen DH, Önnerfjord P, Hansen M, Schmidt H, et al. Granzyme B degraded type IV collagen products in serum identify melanoma patients responding to immune checkpoint blockade. Cancers (Basel). 2020;12(10).Markussen A, Johansen JS, Larsen FO, Theile S, Hasselby JP, Willemoe GL, et al. Nivolumab with or without ipilimumab combined with stereotactic body radiotherapy in patients with metastatic biliary tract cancer: a randomized phase 2 study. Clinical Cancer Research. 2024 Aug 15;30(16):3428–37.Abstract 41 Figure 1Pharmacodynamic changes in C4G associated with treatment response. (A) C4G normalized to baseline, in treatment responders and non-responders, at baseline, second cycle of treatment (cycle 2), and end of treatment (EOT). (B) Percentage of patients with treatment response grouped by C4G change at EOT",
  "authors": [
    {
      "affiliations": [
        "Nordic Bioscience, Herlev, Copenhagen, Denmark"
      ],
      "name": "Martin Rasmussen"
    },
    {
      "affiliations": [
        "Copenhagen University Hospital – Herlev and Gentofte, Herlev, Copenhagen, Denmark",
        "Copenhagen University, Faculty of Health and Medical Sciences, Copenhagen, Denmark"
      ],
      "name": "Inna M Chen"
    },
    {
      "affiliations": [
        "Copenhagen University Hospital – Herlev and Gentofte, Herlev, Copenhagen, Denmark"
      ],
      "name": "Julia S Johansen"
    },
    {
      "affiliations": [
        "Copenhagen University Hospital – Herlev and Gentofte, Herlev, Copenhagen, Denmark"
      ],
      "name": "Susann Theile"
    },
    {
      "affiliations": [
        "Copenhagen University Hospital – Herlev and Gentofte, Herlev, Copenhagen, Denmark"
      ],
      "name": "Alice Markussen"
    },
    {
      "affiliations": [
        "Copenhagen University Hospital – Herlev and Gentofte, Herlev, Copenhagen, Denmark"
      ],
      "name": "Troels Dreier Christensen"
    },
    {
      "affiliations": [
        "Nordic Bioscience, Herlev, Copenhagen, Denmark"
      ],
      "name": "Morten A Karsdal"
    },
    {
      "affiliations": [
        "Nordic Bioscience, Herlev, Copenhagen, Denmark"
      ],
      "name": "Nicholas Willumsen"
    }
  ],
  "title": "41 Pharmacodynamic changes in collagen-derived immune biomarkers predict treatment response in patients with metastatic biliary tract cancer treated with immunotherapy and radiotherapy",
  "uid": "3823f655-2fac-54e0-b7a9-9cb2f914f46e"
}