Use of the Intratumoural Anticancer Drug Tigilanol Tiglate in Two Horses

Thomas De Ridder,Stephanie Williams,Meagan Wheeless,Paul Reddell,Mick Ruppin

doi:10.3389/fvets.2020.00639

Abstract

Tigilanol tiglate is a novel small molecule approved as a veterinary pharmaceutical in Europe for intratumoural treatment of non-metastatic, non-resectable canine mast cell tumors. The drug has a “tumor agnostic” mode of action associated with induction of an acute inflammatory response at the treatment site, immune cell recruitment, and disruption of tumor vasculature. Consequently, tigilanol tiglate has potential in treating a range of tumor types in humans and companion animals. However, it is likely that species-specific dosing and concomitant medication protocols will be required, especially to manage the drug-induced acute inflammatory response at the treatment site. As an initial step in evaluating tigilanol tiglate for treating cutaneous tumors in horses, we developed an equine-specific protocol involving (a) a 30% reduction in intratumoural tigilanol tiglate dose rate compared to that used in dogs, and (b) a regime of concomitant medications to manage the drug-induced acute inflammatory response at the treatment site. Here we report a preliminary study in two horses using the protocol to treat (i) an aggressive fibroblastic sarcoid that had recurred following surgical excision and (ii) a fast-growing peri-ocular squamous cell carcinoma. Clinical response to tigilanol tiglate treatment in these cases was similar to that observed in canine and human patients. Localized inflammation and bruising developed rapidly at the treatment site with haemorrhagic necrosis of the tumor evident within 24 h. Slough of necrotic tumor mass occurred within 6–16 days followed by infill of the tissue defect and full re-epithelialisation of the treatment site with good functional outcome. Drug-induced inflammation and oedema at the treatment site were well controlled by the concomitant medications and largely resolved within 3 days, while the wound that formed following tumor slough healed uneventfully. Both patients displayed minor lethargy during the first 36 h after treatment and localized treatment-site discomfort was apparent over the first 3–5 days. There was no evidence of recurrence of the sarcoid at 93 days, or the squamous cell carcinoma at 189 days. The results from this study support continued development and evaluation of tigilanol tiglate as a potential future treatment option for cutaneous equine tumors.

Highlights

Tigilanol tiglate is a novel small molecule approved in the European Union and United Kingdom as an intratumourally-administered, veterinary pharmaceutical for treatment of non-metastatic, non-resectable canine mast cell tumors [1]
This clinical response is directly related to the mode of action of tigilanol tiglate in tumor destruction and involves localized bruising and inflammation/oedema developing at the treatment site within the first 24 h, followed by haemorrhagic necrosis of the tumor mass and slough of the necrotic tumor leaving a treatment site wound which usually heals uneventfully via secondary intention without the need for bandaging or other interventions [1]
Examination of the eye at day 19 showed it to be normal and unaffected with a well dilated pupil (Figure 3D) and while a small wedge of functional lower eyelid near the medial canthus had been lost following tumor destruction and. In this preliminary study we have shown that an equine-specific treatment protocol based on reduced intratumoural tigilanol tiglate dose and a regime of concomitant anti-inflammatory medications resulted in complete resolution, with good cosmetic and functional healing outcome at the treatment site, of (i) a fibroblastic sarcoid that had recurred following surgical excision 4 months earlier and (ii) a fast growing peri-ocular squamous cell carcinomas (SCCs)

Summary

Introduction

Tigilanol tiglate ( known as EBC-46) is a novel small molecule approved in the European Union and United Kingdom as an intratumourally-administered, veterinary pharmaceutical for treatment of non-metastatic, non-resectable canine mast cell tumors [1]. Tigilanol tiglate is a potent cellular signaling molecule with a multifactorial mode of action that induces (a) a rapid, acute and highly localized inflammatory response in and immediately surrounding the tumor mass, (b) recruitment of immune cells, (c) loss of tumor vasculature integrity and (d) induction of tumor cell death by oncosis [5] At efficacious doses, these processes lead to haemorrhagic necrosis and destruction of the tumor within 7 days followed by resolution of the resulting wound (tissue defect) with good functional and cosmetic outcomes [1]. Sarcoids and squamous cell carcinomas (SCCs) are common skin tumors in horses [6, 7] While they rarely metastasise, both tumor types can be highly invasive into local tissue and they can be difficult to treat effectively with current standards of care [8, 9], when in proximity to vital tissues such as on the head, perineal region and limb joints. They have relatively high recurrence rates and, in the case of sarcoids, a tendency to become refractory to subsequent interventions [6]

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