Defining the pharmacodynamic profile and therapeutic index of NHS-IL12 immunocytokine in dogs with malignant melanoma

Melissa Paoloni, Christina Mazcko, Kimberly Selting, Susan Lana, Lisa Barber, Jeffrey Phillips, Katherine A Skorupski, David Vail, Heather Wilson, Barbara Biller, Anne Avery, Matti Kiupel, Amy Le Blanc, Anna Bernhardt, Beatrice Brunkhorst, Robert Tighe, Chand Khanna

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20 Scopus citations

Abstract

Background: Interleukin (IL)-12 is a pro-inflammatory cytokine that mediates T-helper type 1 responses and cytotoxic T-cell activation, contributing to its utility as anti-cancer agent. Systemic administration of IL-12 often results in unacceptable toxicity; therefore, strategies to direct delivery of IL-12 to tumors are under investigation. The objective of this study was to assist the preclinical development of NHS-IL12, an immunocytokine consisting of an antibody, which targets necrotic tumor regions, linked to IL-12. Specifically this study sought to evaluate the safety, serum pharmacokinetics, anti-tumor activity, and immune modulation of NHS-IL12 in dogs with naturally occurring cancers. Methodology/Principal Findings: A rapid dose-escalation study of NHS-IL12 administered subcutaneously to dogs with melanoma was conducted through the Comparative Oncology Trials Consortium (COTC). Eleven dogs were enrolled in four dose-escalation cohorts; thereafter, an additional seven dogs were treated at the defined tolerable dose of 0.8 mg/m<sup>2</sup>. The expanded cohort at this fixed dose (ten dogs in total) was accrued for further pharmacokinetics and pharmacodynamics assessment. NHS-IL12 levels, serum cytokine concentrations, and peripheral blood mononuclear cell characterization (post-treatment) and draining lymph node immune profiling, and tumor biopsies (pre- and post-treatment) were collected. Adverse events included thrombocytopenia, liver enzymopathies, fever, and vasculitis. Correlation between interferon (IFN)-γ induction, adverse events, and NHS-IL12 exposure (maximum concentration and area under the concentration-time curve) were dose-dependent. Serum IL-10 levels and intratumoral CD8<sup>+</sup> populations increased after treatment. Partial responses, according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, were observed in two dogs treated with NHS-IL12 0.8 mg/m<sup>2</sup> and 1.6 mg/m<sup>2</sup>. Conclusions/Significance: NHS-IL12 was administered safely to dogs with melanoma and both immunologic and clinical activity was observed. This study successfully defined a narrow therapeutic window for systemic delivery of NHS-IL12 via the subcutaneous route. Results will inform the design and implementation of first-in-human clinical trials of NHS-IL12 in cancer patients.

Original languageEnglish (US)
Article numbere0129954
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 19 2015

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Paoloni, M., Mazcko, C., Selting, K., Lana, S., Barber, L., Phillips, J., Skorupski, K. A., Vail, D., Wilson, H., Biller, B., Avery, A., Kiupel, M., Le Blanc, A., Bernhardt, A., Brunkhorst, B., Tighe, R., & Khanna, C. (2015). Defining the pharmacodynamic profile and therapeutic index of NHS-IL12 immunocytokine in dogs with malignant melanoma. PLoS One, 10(6), [e0129954]. https://doi.org/10.1371/journal.pone.0129954