Defining the Pharmacodynamic Profile and Therapeutic Index of NHS-IL12 Immunocytokine in Dogs with Malignant Melanoma

Abstract

BackgroundInterleukin (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 FindingsA 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/SignificanceNHS-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.

The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors

“…For the last two decades, various groups, including our own, have worked on the engineering of antibody‐IL12 fusions, since the heterodimeric nature of IL12 poses various opportunities for protein engineering, leading to formats with different pharmacokinetic and pharmacodynamic properties . Two antibody‐IL12 fusions have recently entered clinical trials for treatment of patients with cancer: BC1‐IL12 and NHS‐IL12 (NCT01417546) . Both fusion proteins are based on intact immunoglobulin structures.…”

“…[28][29][30] Two antibody-IL12 fusions have recently entered clinical trials for treatment of patients with cancer: BC1-IL12 16 and NHS-IL12 (NCT01417546). 31 Both fusion proteins are based on intact immunoglobulin structures. However, antibody fragments may be preferable for the generation of IL12 fusion proteins, in order to achieve a more rapid clearance from circulation and better tumor:organ ratios.…”

Defining the Value of a Comparative Approach to Cancer Drug Development

“…(15) Pharmacokinetic and pharmacodynamic endpoints, in the form of serum IFN-gamma, IL-10 levels and intratumoral CD8+ lymphocytes, were assessed alongside clinical measures of response and toxicity. This study provided data that directly informed the design of the ongoing Phase 1 human trial of this agent (NCT01417546).…”

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

“…The COTC operates as a platform for collaborative work between the NCI and extramural academic comparative oncology centers to design and execute clinical studies in dogs with cancer. Support for (87)(88)(89). COTC trials do not focus exclusively on small molecules or biologic agents; instead, they can be designed and implemented to answer a range of drug development questions that are key to the forward progress of an agent or group of candidate molecules, medical devices, or molecular profiling platforms.…”