Recent clinical trials of cancer immunogene therapy in companion animals

Table 1 Veterinary cancer immunogene therapy trials 2014-2016

No.	Genes	Tumor	Vector	Mode	Results	Ref.
1	hIL-2 + hGM-CSF cIFN-β + HSV-tk	MEL	Plasmid lipofection: HSV-tk + IFN-β + GCV. Plasmid lipofection: hIL-2 and hGM-CSF	In vivo (SG) + (IFN-β) - i.t. In vivo (hIL-2 + hGM-CSF) + (TV) - s.c./+ SX	Combined treatment (n = 301)/surgery controls (n = 162). Complete surgery arms: Local disease-free patients: 83%/11%. Metastasis-free patients: 89%/44%. Median survival: > 2211 d/109 d. Metastasis-free median survival: > 2211 d/134 d	Finocchiaro et al[8]
2	tthIL12	SCC MEL	Plasmid/EGT	In vivo - i.t. EGT	(n = 4) Dose escalation and safety. Two confirmed local and distant responses. No severe side effects	Cutrera et al[9]
3	cIL-12	AMB, PCY, SCC, STS	Naked plasmid + bleomycin/gemcitabine EGT	In vivo - i.t./+ CHT	(n = 13) 2 CR, 4 PR, 5 SD, 2 PD. No severe side effects	Cutrera et al[12]
4	hIL12	MCT	Naked plasmid + cisplatin or bleomycin electrotransfer	In vivo - i.t./+ CHT	(n = 18) 13 CR, 2 PR, 1 SD, 2 PD. No severe side effects	Cemazar et al[14]
5	hIL12	FSA, MAC, MCT, OSA, SCC, SCH	Plasmid/EGT	In vivo - i.t.	(n = 9) Safety studies and demonstration of immunogenic and anti-angiogenic effects. No significant clinical benefits	Cicchelero et al[10]
6	hIL12	ADC, FSA, MEL, OSA, SCH	Plasmid/EGT + metronomic cyclophosphamide	In vivo - i.t. EGT/+ metronomic CHT	(n = 6) No significant unwanted side effects. Combined therapy slowed down tumor progression and improved QOL	Cicchelero et al[13]
7	fIL-2	FSA	Canary pox virus	In vivo - p.t.	Combined treatment (n = 25)/Surgery + brachytherapy controls (n = 23). Disease-free patients: 41%/72%. Median survival: > 730 d/287 d	Jas et al[11]
8	eIL-12 + eIL-18 hgp100 htyr	MEL	Plasmid like	In vivo - i.m./p.t.	(n = 27) No differences between eIL-12 + eIL-18 without (n = 9) or with either hgp100 (n = 9) or htyr (n = 9). Tumor size reduction on day 120 approximately 20%	Mählmann et al[15]
9	CSPG4	MEL	Plasmid/EGT	In vivo - i.m./ + SX	(n = 14) VAC/(n = 13) CTR Median survival: VAC 532 d/CTR 205 d	Riccardo et al[23]
10	hp62	MAC	Plasmid	In vivo - i.m.	(n = 7) 5PR (50%-75% reduction) 2 SD. Safety verified	Gabai et al[22]
11	htyr	MEL	Naked plasmid - Jet injection	In vivo - i.m./ + SX ± RX	Retrospective study (n = 38). Responding patients median survival: 870 d. Non-responding patients median survival: 240 d	McLean et al[19]
12	htyr	MEL	Naked plasmid - Jet injection	In vivo - i.m./ + SX ± RX	Retrospective study (n = 32). Median survival: 335 d. Progression-free median survival: 160 d	Treggiari et al[20]
13	CSPG4	MEL	Plasmid/EGT	In vivo - i.m./ + SX	(n = 23) VAC/(n = 19) CTR Median survival: VAC 684 d/CTR 220 d	Piras et al[24]
14	htyr	MEL	Naked plasmid - Jet injection	In vivo - i.m./ + SX ± RX	Retrospective study (n = 24). Eleven percent of manageable post-vaccination adverse effects. Safety verified. Forty-two percent died of unrelated causes or still alive	Sarbu et al[18]

The No. 1-8 genes are cytokines; the No. 9-14 genes are antigens; the tumors in No. 1-6 and 9-13 are canine; the tumors in No. 7 and 14 are feline; the tumors in No. 8 is equine. ADC: Adenocarcinoma; AMB: Acanthomatous ameloblastoma; FSA: Fibrosarcoma; MAC: Mammary adenocarcinoma; MCT: Mast cell tumor; MEL: Melanoma; PCY: Plasmocytoma; OSA: Osteosarcoma; SCC: Squamous cell carcinoma; SCH: Schwannoma; STS: Soft tissue sarcoma; CSPG4: Chondroitin sulfate proteoglycan-4; GM-CSF: Granulocyte macrophage colony-stimulating factor; gp100: Glycoprotein 100; HSV-tk: Herpes simplex thymidine kinase; IFN-β: Interferon-β; IL: Interleukin; p62: Protein 62; tyr: Tyrosinase; CR: Complete response; CTR: Control; GT: Gene therapy; PR: Partial response; SD: Stable disease; GCV: Ganciclovir; SG: Suicide gene; TV: Tumor vaccine; VAC: Vaccinated; i.m.: Intramuscular, i.t.: Intratumoral; p.t.: Peritumoral; s.c.: Subcutaneous; CHT: Chemotherapy; RX: Radiotherapy; SX: Surgical excision; c: Canine; e: Equine; f: Feline; h: Human; tt: Tumor targeted.