Clinical Trials of Immunogene Therapy for Spontaneous Tumors in Companion Animals

Table 1

Canine cancer immunogene therapy trials.

#	Genes	Tumor	Vector	Mode	Results	Authors/year/references
	Cytokines	Canine
1	hIL-2	MEL	Irradiated hIL-2 producing xenogeneic cells made by plasmid transfection	Ex vivo/p.t./; +SX + RX	( = 16) NR, 480 d. Control: 1/treated: 6.; Median survival: treated: 270 d/control: 75 d	Quintin-Colonna et al., 1996 [2]
2	cIL-2 + enterotoxin-A	STS	Plasmid lipofection	In vivo/i.t.; + SX	( = 16) 3 CR, 1 PR, 1 SD (84 d). Responders survival: >540 d w/o relapse.	Thamm et al., 2003 [33]
3	cIL-2	OSA lung metastases	Plasmid lipofection	In vivo/i.v./; +SX + CHT	( = 20) 84 d: 1 CR, 2 PR, 4 SD. Median survival (s IV): treated: 82 d/Hist. Surg. controls: 58 d	Dow et al., 2005 [36]
4	hGM-CSF	MEL; FSA; OSA; HGS	Irradiated hGM-CSF producing autologous tumor cells plasmid transferred by gene gun	Ex vivo/i.d./; NAT	MEL ( = 10) 1 CR (300 d), 1 PR (300 d), 1 NED (250 d), 1 SD (125 d); FSA ( = 3) 1 PR, 1 NED (175 d)	Hogge et al., 1998 [13]
5	cGM-CSF + enterotoxin-B	MEL	Plasmid lipofection	In vivo/i.t., p.t., i.l.n./NAT	( = 12) median survival (stage III): treated: 168 d/Hist. Surgery controls: 105 d	Dow et al., 1998 [14]
6	hGM-CSF	LYP	Plasmid lipofection	In vivo/i.d./; +CHT	Vaccine ( = 26)/placebo ( = 26). Median survival 474 d/342 d	Turek et al., 2007 [40]
7	hIL-2 +; hGM-CSF; HSV-tk	MEL	Plasmid lipofection: HSV-tk + GCV. Irradiated xenogeneic hIL-2 and hGM-CSF producing cells made by plasmid lipofection	In vivo (SG)/i.t., Ex vivo (CPXC)/i.t./NAT	Combined treatment ( = 45)/surgery controls ( = 23). Median survival: 160 d/82 d. Metastasis-free median survival: >509 d/133 d. Combined treatment: CR = 16%, PR = 31%, SD = 27%, PD = 27%.	Finocchiaro et al., 2008 [28]
8	hIL-2 +; hGM-CSF HSV-tk	MEL	Plasmid lipofection: HSV-tk + GCV. Irradiated xenogeneic hIL-2 and hGM-CSF producing cells made by plasmid lipofection	In vivo (SG) − i.t./Ex vivo (CPXC) + (TV) − s.c./+SX	Combined treatment ( = 100)/surgery controls ( = 51): local disease-free patients: 58%/6%. Metastasis-free patients: 78%/43%. Median survival: >1312 d/78 d. Metastasis-free median survival: >1312 d/112 d.	Finocchiaro and Glikin, 2008 [29]
9	hIL-2 +; hGM-CSF; HSV-tk	MEL	Plasmid lipofection: HSV-tk + GCV. Irradiated xenogeneic hIL-2 and hGM-CSF producing cells made by plasmid lipofection	In vivo (SG) − i.t.; Ex vivo (CPXC) + (TV) − s.c./+SX	Combined treatment ( = 283)/surgery controls ( = 135). Complete surgery arms: local disease-free patients: 81%/13%. Metastasis-free patients: 84%/32%. Median survival: >2848 d/99 d. Metastasis-free median survival: >2848 d/99 d.	Finocchiaro and Glikin, 2012 [30]
10	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 ( = 301)/surgery controls ( = 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., Submitted [31]
	Genes; Cytokines	Tumor; Canine
11	hIL-2 +; hGM-CSF; cIFN-β +; HSV-tk	STS	Plasmid lipofection: HSV-tk + IFN-β + GCV. Irradiated xenogeneic hIL-2 and hGM-CSF producing cells made by plasmid lipofection	In vivo (SG) + (IFN-β) − i.t.; Ex vivo (CPXC) + (TV) − s.c/+SX.	( = 11) 5 survived >2 years, 4 survived >1 year	Finocchiaro et al., 2011 [34]
12	hIL-2 +; hGM-CSF; cIFN-β +; HSV-tk	OSA	Plasmid lipofection: HSV-tk + IFN-β + GCV. Irradiated xenogeneic hIL-2 and hGM-CSF producing cells made by plasmid lipofection	In vivo (SG) + (IFN-β) − i.t.; Ex vivo (CPXC) + (TV) − s.c/+SX.	( = 6) 2 survived > 1 year	Finocchiaro et al., 2012 [37]
13	hIFN-γ	ASC	Adenovirus	In vivo − p.t.; + (TV) − s.c./; +SX.	( = 1) feasible. Disease-free survival >450 d	Pluhar et al., 2010 [46]
14	fIL-12 +; bleomycin	SCC; AMB; MEL; STS	Naked plasmid + bleomycin electrotransfer	In vivo − i.t./+CHT	( = 5) 2 SSC and AMB resolved (56, 27, 9 months tumor-free).	Reed et al., 2010 [45]
15	hIL-12	MCT; PHS; OSA; MAC	Naked plasmid electrotransfer	In vivo − i.m/; ±SX ± CHT	( = 6) CR: 2 of 3 MCT. SD: 1 PHS and 1 OSA.	Cemazar et al., 2011 [47]
16	hIL-12	MCT	Naked plasmid electrotransfer	In vivo − i.t./; ±SX ± CHT	( = 8) 50% median reduction of tumor volumes	Pavlin et al., 2011 [48]
	Antigens	Canine
17	hTyr	MEL; oral	Naked plasmid − Jet injection	In vivo − i.m./; ±SX ± RX	( = 9) 1 CR, 2 NED, 1 SD (14 d)/median survival: 389 d. Historical controls (s II 150 d, s III 60 d). Humoral antibodies: 3/9.	Bergman et al., 2003 [16]; Liao et al., 2006 [17]
18	hTyr/mTyr; mgp75/; hGM-CSF	MEL	Naked plasmid − Jet injection	In vivo − i.m./; ±SX ± RX	Different combinations and doses. Median survival stages II-III ( = 33) w/locoregional control: 569 d. 25/33 still alive at submission.	Bergman et al., 2006 [20]
19	hTyr	MEL; oral	Naked plasmid − Jet injection	In vivo − i.m./; +SX ± RX	( = 58) death attributable to MM ( = 15), to other causes ( = 16). Median survival: >750 d. Historical controls ( = 53): 324 d.	Grosenbaugh et al., 2011 [18]
20	mTyr	MEL; digital	Naked plasmid − Jet injection	In vivo − i.m./; +SX + RX	( = 58) median survival: >476 d. Surgery only historical controls: 365 d	Manley et al., 2011 [21]
	Antigens	Canine
21	hTyr	MEL	Naked plasmid − Jet injection	In vivo − i.m/; +SX ± RX	( = 22) no differences in PFS, DFI, or median survival with surgery controls ( = 23)	Ottnod et al., 2013 [22]
22	hgp100	MEL	Autologous adenovirus transduced dendritic cells	Ex vivo − s.c./; +SX + RX	( = 3) survival ranging 210–1440 d	Gyorffy et al., 2005 [23]
23	hgp100	MEL	Irradiated allogeneic hgp100 expressing tumor cells plasmid transferred by gene gun	Ex vivo − i.d./; NAT	( = 34) median survival: responders (CR, PR, SD) ( = 12), 337 d/nonresponders ( = 20), 95 d	Alexander et al., 2006 [24]
24	cTERT; cTERT-LTB	LYP	Naked plasmid electroporation + adenovirus 6	In vivo − i.m./; +CHT	( = 14) GT + CHT/( = 8) CHT.; Median survival: >96 wks/28 wks.; Time to first relapse: >26 wks/12 wks.	Peruzzi et al., 2010 [42]
25	cTERT	LYP	Electroporation + Adenovirus	In vivo − i.m./; +CHT	( = 21) VAC/( = 21) CTR median survival: VAC 76.1 w/CTR 29.3 w	Gavazza et al., 2013 [43]
26	Emm55	LYP	Plasmid/electroporation	Ex vivo − i.v./; ±CHT	( = 7) 1 CR > 555 d,; 6 PR, 3 extended survival >2X	Lawman et al., 2008 [41]
27	CSPG4	MEL	Plasmid/electroporation	In vivo − i.m./.; +SX.	( = 14) VAC/( = 13) CTR median survival: VAC 76.1 w/CTR 29.3 w	Riccardo et al., 2014 [27]
28	cNHL-mRNA	LYP	Combination chemotherapy + NHL-mRNA loaded electroporation of CD40-activated B cells.	Ex vivo RNA transfer/; +CHT	( = 19) significant increase of lymphoma-specific survival following salvage therapy	Sorenmo et al., 2011 [44]
	Specific ligands	Canine
29	hCD40L	MEL	Adenovirus	In vivo − i.t./.; ±SX.	( = 2) feasible and manageable toxicity; 1 NED 401 d 1 PR >150 d	von Euler et al., 2008 [25]
30	hCD40L	MEL	Adenovirus	In vivo − i.t./.; ±SX.	( = 19) median survival: responders (CR, PR, SD) ( = 17), 160 d/nonresponders ( = 2)	Westberg et al., 2013 [26]
31	hFasL	MEL	Plasmid lipofection	In vivo − i.t./; ±SX ± RX	( = 5) GT: 3 TR, 1 SD/CT: 2 CR, 2 PR Survival: 168–574 d	Bianco et al., 2003 [15]
32	hFasL	OSA	Adenovirus	In vivo − i.t./; +SX	( = 48) Ad-FasL-mediated tumor inflammation improved median survival (score 2/3: 359 d; controls: 221 d)	Modiano et al., 2012 [38]

AMB, acanthomatous ameloblastoma; ASC, astrocytoma; FSA, fibrosarcoma; HGS, hemangiosarcoma; LYP, lymphoma; MAC, mammary adenocarcinoma; MCT, mast cell tumor; MEL: melanoma; OSA, osteosarcoma; PHS, pulmonary histiocytic sarcoma; SCC, squamous cell carcinoma; STS, soft tissue sarcoma; CD40L, CD40 ligand; Emm55, Streptococcus pyogenes serotyping antigen; FasL, Fas ligand; GM-CSF, granulocyte macrophage colony stimulating factor; gp100, glycoprotein 100; gp75, glycoprotein 75; HSV-tk, herpes simplex thymidine kinase; IFN-β, interferon-β; IFN-γ, interferon-γ; IL-12, interleukin-12; IL-2, interleukin-2; LTB, Escherichia coli heat labile enterotoxin; NHL-mRNA, non-Hodgkin lymphoma messenger RNA; TERT, telomerase reverse transcriptase; Tyr, tyrosinase; CR, complete response; CTR, control; DFI, disease-free interval; GT, gene therapy; NED, no evidence of disease; NR, no relapse; PFS, progression-free survival; PR, partial response; SD, stable disease; CPXC, cytokine producing xenogeneic cells; GCV, ganciclovir; SG, suicide gene; TV, tumor vaccine; VAC, vaccinated; i.d., intradermal; i.l.n., intralymph node; i.m., intramuscular, i.t., intratumoral; i.v., intravenous; p.t., peritumoral; s.c., subcutaneous; CHT, chemotherapy; NAT, no additional treatment during or following gene therapy; RX, radiotherapy; SX, surgical excision; d, days; wks, weeks; prefixes: c, canine; e, equine; f, feline; h, human; m, murine.