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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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

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Pharmacodynamics
pharmacology
Interleukin-12
melanoma
Melanoma
Dogs
interleukin-12
therapeutics
neoplasms
dogs
dosage
Tumors
Therapeutics
pharmacokinetics
Neoplasms
cytokines
Pharmacokinetics
vasculitis
thrombocytopenia
antineoplastic agents

ASJC Scopus subject areas

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

Cite this

Paoloni, M., Mazcko, C., Selting, K., Lana, S., Barber, L., Phillips, J., ... 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

Defining the pharmacodynamic profile and therapeutic index of NHS-IL12 immunocytokine in dogs with malignant melanoma. / Paoloni, Melissa; Mazcko, Christina; Selting, Kimberly; Lana, Susan; Barber, Lisa; Phillips, Jeffrey; Skorupski, Katherine A; Vail, David; Wilson, Heather; Biller, Barbara; Avery, Anne; Kiupel, Matti; Le Blanc, Amy; Bernhardt, Anna; Brunkhorst, Beatrice; Tighe, Robert; Khanna, Chand.

In: PLoS One, Vol. 10, No. 6, e0129954, 19.06.2015.

Research output: Contribution to journalArticle

Paoloni, M, Mazcko, C, Selting, K, Lana, S, Barber, L, Phillips, J, Skorupski, KA, 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, vol. 10, no. 6, e0129954. https://doi.org/10.1371/journal.pone.0129954
Paoloni, Melissa ; Mazcko, Christina ; Selting, Kimberly ; Lana, Susan ; Barber, Lisa ; Phillips, Jeffrey ; Skorupski, Katherine A ; Vail, David ; Wilson, Heather ; Biller, Barbara ; Avery, Anne ; Kiupel, Matti ; Le Blanc, Amy ; Bernhardt, Anna ; Brunkhorst, Beatrice ; Tighe, Robert ; Khanna, Chand. / Defining the pharmacodynamic profile and therapeutic index of NHS-IL12 immunocytokine in dogs with malignant melanoma. In: PLoS One. 2015 ; Vol. 10, No. 6.
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AU - Mazcko, Christina

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AU - Barber, Lisa

AU - Phillips, Jeffrey

AU - Skorupski, Katherine A

AU - Vail, David

AU - Wilson, Heather

AU - Biller, Barbara

AU - Avery, Anne

AU - Kiupel, Matti

AU - Le Blanc, Amy

AU - Bernhardt, Anna

AU - Brunkhorst, Beatrice

AU - Tighe, Robert

AU - Khanna, Chand

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N2 - 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/m2. 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+ 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/m2 and 1.6 mg/m2. 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.

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