Abstract
Bovine papillomaviruses types 1 and 2 (BPV1, BPV2) commonly induce skin tumours termed sarcoids in horses and other equids. Sarcoids seriously compromise the health and welfare of affected individuals due to their propensity to resist treatment and reoccur in a more severe form. We have developed influenza (Flu) A and B virus vectors that harbour a truncated NS1 gene (iNS) assuring interferon induction and co-express shuffled BPV1 E6 and E7 antigens for sarcoid immunotherapy. In a safety trial involving 12 healthy horses, intradermal administration of iNSA/E6E7equ and iNSB/E6E7equ was well tolerated, with the only transient side effect being mild fever in four horses. Repeated screening of secretions and faeces by RT-PCR and plaque assay revealed no virus shedding, thus also confirming biological safety. In a patient trial involving 29 horses bearing BPV1-induced single or multiple sarcoids, at least one lesion per horse was intratumourally injected and then boosted with iNSA/E6E7equ and/or iNSB/E6E7equ. The treatment induced a systemic antitumour response as reflected by the synchronous regression of injected and non-injected lesions. Irrespective of vaccination schemes, complete tumour regression was achieved in 10/29 horses. In 10/29 horses, regression is still ongoing (May 2021). Intriguingly, scrapings collected from former tumour sites in two patients tested negative by BPV1 PCR. Nine severely affected individuals with a history of unsuccessful therapeutic attempts did not (6/29) or only transiently (3/29) respond to the treatment. INSA/E6E7equ and iNSB/E6E7equ proved safe and effective in significantly reducing the tumour burden even in severe cases.
Highlights
Equine sarcoids are non-metastasising, yet locally aggressive cutaneous fibropapillomas induced by bovine delta-papillomaviruses of type 1, 2 and possibly type 13 (BPV1, BPV2, BPV13) [1, 2]
Results iNSA/E6E7equ and iNSB/E6E7equ are genetically stable and express E6/E7 transgenes iNSA and iNSB influenza viruses harbouring shuffled BPV1 E6 and E7 coding sequences were obtained by genetic engineering
INSA/E6E7equ- and iNSB/ E6E7equ-infected cells tested positive for E6E7, NP and beta actin expression
Summary
Equine sarcoids are non-metastasising, yet locally aggressive cutaneous fibropapillomas induced by bovine delta-papillomaviruses of type 1, 2 and possibly type 13 (BPV1, BPV2, BPV13) [1, 2]. The respective oncoproteins are expressed throughout tumour development and act in a combined manner They assure the survival of infected host cells by inducing their immortalisation, hyperproliferation and anoikis-independent growth [10,11,12]. The specific partial deletion resulted in iNS-based vectors, which induce high levels of IFN while– unlike the fully deleted NS1 deletion mutants–retaining the ability to replicate efficiently in IFN-sensitive tumour cells In this context, we have previously shown that such partly deleted mutants have better antitumour properties and are less sensitive to the growth inhibitory effects of IFN [46]. We report on the generation of these viruses, their safety in tumour-free horses, and their therapeutic efficacy in sarcoid-affected equine patients
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