Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies

Stephen M. Ansell, Ian Flinn, Matthew H. Taylor, Branimir I. Sikic, Joshua Brody, John Nemunaitis, Andrew Feldman, Thomas R. Hawthorne, Tracey Rawls, Tibor Keler, Michael J. Yellin

    Research output: Contribution to journalArticle

    Abstract

    CD27, a costimulatory molecule on T cells, induces intracellular signals mediating cellular activation, proliferation, effector function, and cell survival on binding to its ligand, CD70. Varlilumab, a novel, first-in-class, agonist immunoglobulin G1 anti-CD27 antibody, mediates antitumor immunity and direct killing of CD27+ tumor cells in animal models. This first-inhuman, dose-escalation, and expansion study evaluated varlilumab in patients with hematologic malignancies. Primary objectives were to assess safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. In a 3 + 3 dose-escalation design, 30 patients with B-cell (n = 25) or T-cell (n = 5) malignancies received varlilumab (0.1, 0.3, 1, 3, or 10 mg/kg IV) as a single dose with a 28-day observation period, followed by weekly dosing (4 doses per cycle, up to 5 cycles, depending on tumor response). In an expansion cohort, 4 additional patients with Hodgkin lymphoma received varlilumab at 0.3 mg/kg every 3 weeks (4 doses per cycle, up to 5 cycles). No dose-limiting toxicities were observed. Treatment-related adverse events, generally grade 1 to 2, included fatigue, decreased appetite, anemia, diarrhea, and headache. Exposure was linear and dose-proportional across dose groups and resulted in increases in proinflammatory cytokines and soluble CD27. One patient with stage IV Hodgkin lymphoma experienced a complete response and remained in remission at >33 months with no further anticancer therapy. These data support further investigation of varlilumab for hematologic malignancies, particularly in combination approaches targeting nonredundant immune regulating pathways. This trial was registered at www.clinicaltrials.gov as #NCT01460134.

    Original languageEnglish (US)
    Pages (from-to)1917-1926
    Number of pages10
    JournalBlood Advances
    Volume4
    Issue number9
    DOIs
    StatePublished - May 12 2020

    ASJC Scopus subject areas

    • Hematology

    Fingerprint Dive into the research topics of 'Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies'. Together they form a unique fingerprint.

  • Cite this

    Ansell, S. M., Flinn, I., Taylor, M. H., Sikic, B. I., Brody, J., Nemunaitis, J., Feldman, A., Hawthorne, T. R., Rawls, T., Keler, T., & Yellin, M. J. (2020). Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies. Blood Advances, 4(9), 1917-1926. https://doi.org/10.1182/bloodadvances.2019001079