First-in-Human Phase I Trial of a Tumor-Targeted Cytokine (NHS-IL12) in Subjects with Metastatic Solid Tumors

Abstract

The NHS-IL12 immunocytokine is composed of two IL12 heterodimers fused to the NHS76 antibody. Preclinical studies have shown that this antibody targets IL12 to regions of tumor necrosis by binding histones on free DNA fragments in these areas, resulting in enhanced antitumor activity. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and pharmacokinetics of NHS-IL12 in subjects with advanced solid tumors. Subjects ( = 59) were treated subcutaneously with NHS-IL12 in a single ascending-dose cohort followed by a multiple ascending-dose cohort ( = 37 with every 4-week dosing). The most frequently observed treatment-related adverse events (TRAE) included decreased circulating lymphocytes, increased liver transaminases, and flu-like symptoms. Of the grade ≥3 TRAEs, all were transient and only one was symptomatic (hyperhidrosis). The MTD is 16.8 μg/kg. A time-dependent rise in IFNγ and an associated rise in IL10 were observed following NHS-IL12. Of peripheral immune cell subsets evaluated, most noticeable were increases in frequencies of activated and mature natural killer (NK) cells and NKT cells. Based on T-cell receptor sequencing analysis, increases in T-cell receptor diversity and tumor-infiltrating lymphocyte density were observed after treatment where both biopsies and peripheral blood mononuclear cells were available. Although no objective tumor responses were observed, 5 subjects had durable stable disease (range, 6-30+ months). NHS-IL12 was well tolerated up to a dose of 16.8 μg/kg, which is the recommended phase II dose. Early clinical immune-related activity warrants further studies, including combination with immune checkpoint inhibitors.

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

“…The toxicological profile, as evidenced by elevated levels of transaminases and decreased White Blood Cells count, was similar for both therapeutics. 16,17 In mice, L19-mIL12 was very well tolerated at a dose of 12 μg, which is equivalent to the human dose of 2 mg, under consideration of the body surface scaling factor. 16,17 The lack of toxicity was corroborated by the absence of weight loss (Figs.…”

“…16,17 In mice, L19-mIL12 was very well tolerated at a dose of 12 μg, which is equivalent to the human dose of 2 mg, under consideration of the body surface scaling factor. 16,17 The lack of toxicity was corroborated by the absence of weight loss (Figs. 3b and 3c) and by the histopathological analysis of organs by necropsy (Supporting Information Fig.…”

“…[13][14][15] Some antibody-cytokine fusions are currently being investigated in the clinic for the treatment of different types of malignancies. [16][17][18][19][20][21][22][23][24] Interleukin-12 (IL12) is a heterodimeric cytokine consisting of the p40 and p35 subunits, linked by a disulfide bond. 25,26 The protein is predominantly produced by antigenpresenting cells (APCs) upon recognition of "danger signals" such as pathogen-associated molecular patterns (PAMPs).…”

Immune regulation and cytotoxic T cell activation of IL-10 agonists – Preclinical and clinical experience

“…In comparison, patients treated with i.v. bolus of recombinant IL-12 have a transient rise in serum IFNγ up to 1600 pg/mL [93] and patients on antibody-coupled NHS-IL-12 had spikes of IFNγ up to 20 ng/mL [94]. Pegilodecakin also induced sustained elevation of IL-18.…”

Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade

“…IL2-antibody products[14,24,39,40] might benefit from the transient and selective inhibition of key intracellular mediators of their activity.…”