{
  "abstract": "Background Intravenous dosing of the anti-CD137 (4-1BB) agonist monoclonal antibody urelumab is limited to 8 mg flat doses due to liver toxicity, thus reducing bioavailability. Here we explored intratumoral delivery of urelumab to increase bioavailability at the tumor site while reducing systemic exposure, in combination with systemic nivolumab (clinical trial INTRUST, NCT03792724).Methods We delivered three intratumoral injections of urelumab 8 mg, alternating with intravenous nivolumab 240 mg every two weeks, followed by nivolumab maintenance at 480 mg every 4 weeks ( figure 1). Patients presenting solid tumors with known sensitivity to PD-1/PD-L1 blockade were treated in two cohorts (Cohort A: PD-1/PD-L1 blockade naive; Cohort B: progression following PD-1/PD-L1 blockade). The first six patients were treated in a safety dose-escalation cohort. We collected fresh tumor biopsies with each intratumoral injection and performed multiplex tissue immunofluorescence and bulk RNA-seq of these specimens. Additionally, a comprehensive series of cytokines in sequential plasma samples was analyzed.Results Among 31 treated patients, we observed two objective responses and a 67.7% disease control rate. Treatment was well tolerated, and no dose-limiting liver toxicity was observed ( figure 1). Serial biopsies revealed urelumab-induced increases in T lymphocyte density and CD137 expression. The increase in tumor-infiltrating CD8 T cells was associated with durable clinical benefit (figure 2). RNA-seq results were consistent with such pharmacodynamic changes. Finally, we observed a significant plasmatic elevation of T-cell activation cytokines, denoting immune activation by intratumoral urelumab.Conclusions Intratumoral delivery of urelumab is feasible, safe, and induces favorable immunopharmacodynamic effects in serial biopsies and in peripheral blood. Our results support the development of next-generation CD137 (4-1BB) agonists in Phase-2/3 clinical trials, especially considering those with concomitant PD(L)-1 blockade.Abstract 531 Figure 1Treatment, safety and clinical outcomes. (A) Schematic time course representation of treatment and collection of samples. (B) Swimmer plot of the patients in the trial, specifying cohort, baseline PD-L1 status, and tumor type. (C) Summary of the main treatment-related and -unrelated side effectsAbstract 531 Figure 2Treatment-associated changes in the tumor microenvironment. A) mIF images with the indicated markers. B) Quantitative PD-L1 expression. C-D) Percentages of indicated markers over time. E-F) Microphotographs of CD8 and CD137 expression, and changes over time. G) Comparison of disease control and CD8 increases",
  "authors": [
    {
      "affiliations": [
        "Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Miguel F Sanmamed"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Carlos E De Andrea"
    },
    {
      "affiliations": [
        "CIMA Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "David Ruiz-Guillamon"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Maria E Rodriguez-Ruiz"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Ignacio Ortego"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Iñaki Eguren-Santamaria"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Alberto Benito"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Álvaro López-Janeiro"
    },
    {
      "affiliations": [
        "CIMA Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Jose Gonzalez-Gomariz"
    },
    {
      "affiliations": [
        "Yale University, New Haven, CT, USA"
      ],
      "name": "Maria Villalba"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Mariano Ponz-Sarvise"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Jose M Lopez-Picazo"
    },
    {
      "affiliations": [
        "CIMA Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Gabriel Gomis"
    },
    {
      "affiliations": [
        "CIMA Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Paula Molero"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Raluca Alexandru"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Inmaculada Rodriguez"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Sandra Sanchez-Gregorio"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain"
      ],
      "name": "Jose L Perez-Gracia"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Pamplona, Navarra, Spain",
        "CIMA Universidad de Navarra, Pamplona, Navarra, Spain",
        "University of Oxford, Pamplona, Navarra, Spain"
      ],
      "name": "Ignacio Melero"
    }
  ],
  "title": "531 A multi-cohort phase 1-2 clinical trial shows safety, feasibility and pharmacodynamic activity of intratumoral injections of the agonist anti-CD137 (4–1BB) mAb urelumab in combination with nivolumab",
  "uid": "f2c34cf2-00e2-5c82-a172-9cc555ad4383"
}