. 2016 Sep 23;173(21):3041–3079. doi: 10.1111/bph.13576

Table 3.

List of PSMA based therapeutics developed with focus on Immunotherapy and radiotherapy

Therapeutic payload	Delivery vector	Targeting ligand	In vitro model	In vivo model	Concluding remarks	References
Immunotherapy
CD‐40 Targeted adenovirus	CD‐40 Targeted adenovirus	N/A	RM1 cells (PSMA+)	N/A	Only combination therapy of Ad5‐huPSMA and Ad5‐IFNγ resulted in delayed growth of RM1‐PSMA tumours by CTL.	(Williams et al., 2012)
CD‐40 Targeted adenovirus	CD‐40 Targeted adenovirus	N/A	RM1 cells (PSMA+)	N/A	Tumours that were PSMA‐ showed a weak inhibition of tumour growth.	(Williams et al., 2012)
DCs treated with recombinant survivin and recombinant PSMA	N/A	N/A	N/A	Patient study	Response Evaluation Criteria In Solid Tumours was 72.7% for the DC group and 45.4% in the control group.	(Xi et al., 2015)
DCs treated with recombinant survivin and recombinant PSMA	N/A	N/A	N/A	Patient study	The median overall survival of patients in the DC vaccine group improved by 11 months compared with the control group	(Xi et al., 2015)
DCs	Adenovirus	N/A	RM1 cells (PSMA+)	N/A	DCs were transduced with Ad‐tPSMA, Ad‐m4‐1BBL and Ad‐tPSMA‐m4‐1BBL.	(Youlin et al., 2013)
DCs	Adenovirus	N/A	RM1 cells (PSMA+)	N/A	Highest level of T‐cell cytotoxicity in RM‐1 cells (~60%) was seen in the group transduced with Ad‐tPSMA‐m4‐1BBL.	(Youlin et al., 2013)
T‐cells	Lentivirus expressing CAR (J591)	N/A	MS1PSMA,H5VPSMA	NOD/SCID mice	The CAR T‐cells were shown to be capable of killing the PMSA+ cells while sparing the PSMA‐ lines in vitro.*	(Santoro et al., 2014)
T‐cells	Lentivirus expressing CAR (J591)	N/A	MS1PSMA,H5VPSMA	NOD/SCID mice	In vivo;full regression of PMSA+ MS1 tumours following dosing of CAR T‐cells 24 days post tumour inoculation.	(Santoro et al., 2014)
T‐cells	Lentivirus expressing anti‐human PSMA	N/A	LNCaP, PC‐3	NOD/SCID, SCID	Specific CTL activity against PC‐3 cells manipulated to express PSMA (PC‐3‐PIP), but not in wild type PC‐3.	(Zuccolotto et al., 2014)
T‐cells	Lentivirus expressing anti‐human PSMA	N/A	LNCaP, PC‐3	NOD/SCID, SCID	In vivo; Detectable metastatic disease 21 post T‐cell injection in control group, with no visible signs of PC‐3 PIP cells after this point in the treated group.	(Zuccolotto et al., 2014)
T‐cells	Retrovirus expressing scFv of anti‐human PSMA	N/A	PC‐3 (PSMA+/−)	BALB/c nude mice	Specific cell lysis of PC‐3PSMA, which was not observed in WT PC‐3 cells.	(Ma et al., 2014)
T‐cells	Retrovirus expressing scFv of anti‐human PSMA	N/A	PC‐3 (PSMA+/−)	BALB/c nude mice	In vivo; In a PC‐3 PSMA xenograft mouse model, 75% of mice treated with T‐cells expressing anti‐PSMA CARs were tumour free 27 days post inoculation.	(Ma et al., 2014)
T‐cells	Bispecific antibody targeting PSMA and PSCA	N/A	PC‐3, LNCap	N/A	*Antibody constructs were able to elicit a T‐cell response and resulted in subsequent lysis of PC‐3PSMA, PC‐3PSCA, PC‐3PSMA/PSCA when co‐cultured with the constructs and inactivated t‐cells.	(Arndt et al., 2014)
Genes encoding ttk and sFLT3L	Adenovirus	N/A	LNCaP, PC‐3, DU‐145, CWR22rv	N/A	Expression of “therapeutic” and viral replication genes and could only take place in cells expression PSMA and PSA.	(Kim et al., 2013)
Genes encoding ttk and sFLT3L	Adenovirus	N/A	LNCaP, PC‐3, DU‐145, CWR22rv	N/A	LNCaP/CWR22rv had higher levels of viral accumulation and cell death when compared with DU‐145/PC‐3.	(Kim et al., 2013)
T‐cells	Bispecific diabody targeting PSMA and CD3	N/A	LNCaP, C4–2, DU‐145	N/A	Only in the presence of PMSA+ cells was there T‐cell activation and expression of CD25 and CD69 in T‐cells.	(Fortmüller et al., 2011)
T‐cells	Bispecific diabody targeting PSMA and CD3	N/A	LNCaP, C4–2, DU‐145	N/A	C4–2 mice treated with T‐cells + PSMA x CD3 diabody showed a lower tumour burden (<200mm³) compared with the control groups (>1500 mm³).	(Fortmüller et al., 2011)
T‐cells	Electroporation of plasmid DNA vaccines encoding PSA and PSMA	N/A	N/A	BALB/C nude	Vaccines were delivered IM followed by electroporation.	(Ferraro et al., 2011)
T‐cells		N/A	N/A	BALB/C nude	Plasmid vaccines induced a strong IFNγ and IL‐2 response by CD4+ and CD8+ T‐cells, with CD4+ also exhibiting a strong TNFα response.	(Ferraro et al., 2011)
T‐cells	DNA fusion vaccines w/PSMA/FrC of tetanus vaccine	N/A	TRAMP‐C1	HHD mice	Fusion vaccines stimulated over 75% specific lysis of cells endogenously expressing PSMA.	(Vittes et al., 2011)
T‐cells	DNA fusion vaccines w/PSMA/FrC of tetanus vaccine	N/A	TRAMP‐C1	HHD mice	In vivo; Specific lysis of PSMA + cells was stimulated by the fusion vaccines in three quarters of mice tested.	(Vittes et al., 2011)
Radiotherapy
²²⁵Ac	Liposomes	J591 antibody/ A10 Aptamer	LnCaP, Mat‐Lu, HUVEC, BT474, and MDA‐MB‐231	N/A	J591‐liposomes were more effective at binding to all cell lines compared with A10‐liposomes.	(Bandekar et al., 2014)
²²⁵Ac	Liposomes	J591 antibody/ A10 Aptamer	LnCaP, Mat‐Lu, HUVEC, BT474, and MDA‐MB‐231	N/A	J591‐liposomes loaded with ²²⁵Ac was also the most cytotoxic liposomal construct tested.	(Bandekar et al., 2014)
¹⁷⁷Lu	N/A	DKFZ‐617 PSMA inhibitor	N/A	Human clinical study	10 patients with chemotherapy resistant and/or hormone refractory prostate cancer were treated with ¹⁷⁷Lu‐DKFZ‐617 PSMA.	(Ahmadzadehfar et al., 2015)
					70% of patients had a PSA decline, with 5 patients showing PSA decline >50%.
					¹⁷⁷Lu‐DKFZ‐617 PSMA also exhibited a low early side effect profile.
¹⁷⁷Lu/⁶⁸Ga	–	DOTAGA‐ffk(Sub‐KuE)	LnCap cells	CD‐1 nu/nu mice	This theranostic allows for combined diagnosis and therapy. The uptake of imaging and therapeutic agent was greatest in the tumour and kidneys (both PSMA expressing) 1 hour post injection in an LNCaP xenograft model (4.95% ID/g for ⁶⁸Ga‐PSMA and 7.96% ID/g for ¹⁷⁷Lu‐PSMA).	(Weineisen et al., 2015)
¹⁷⁷Lu/⁶⁸Ga	–	DOTAGA‐ffk(Sub‐KuE)	LnCap cells	CD‐1 nu/nu mice	Treatment of two patients with metastatic disease was shown to be effective with no side effects detected.	(Weineisen et al., 2015)
¹⁷⁷Lu	N/A	DKFZ‐11 PSMA inhibitor	N/A	Human clinical study	Following treatment, patient showed a radiological response and in addition, PSA levels fell from 38 to 4.6 ng/ml.	(Kratochwil et al., 2015)
¹²⁴I/¹³¹I	N/A	MIP‐1095 PSMA inhibitor	N/A	Human clincal study	16 patients underwent 124I/¹³¹I‐MIP‐1095 treatment. PSA levels fell by >50% in 60.7% of patients treated.	(Zechmann et al., 2014)
¹²⁴I/¹³¹I	N/A	MIP‐1095 PSMA inhibitor	N/A	Human clincal study	84.6% of patients that reported bone pain indicated either a complete or moderate pain relief. There were no significant haematological or renal toxicities reported.	(Zechmann et al., 2014)
¹⁷⁷Lu	N/A	PSMA antibody J591	N/A	Human clinical study	47 hormone refractory patients were treated in a Phase II clinical trial with ¹⁷⁷Lu‐J591. 10.6% AND 36.2% of patients received a ≥ 50% ≥ 30% decrease in PSMA levels respectively.	(Tagawa et al., 2013), (Simone and Hahn, 2013)
¹⁷⁷Lu	N/A	PSMA antibody J591	N/A	Human clinical study	There was a significantly longer survival (P = 0.03) in those patients receiving the maximum tolerated dose (21.8 vs 11.9 months). Patients with low PSMA expression were less likely to respond.	(Tagawa et al., 2013), (Simone and Hahn, 2013)
¹⁷⁷Lu	N/A	DOTA‐3/F11 (PSMA antibody)	C4–2 and DU145 cells	SCID mouse (C4–2 xenograft model)	Imaging agents showed T1/2 of >7 days in vivo. A single dose of ¹⁷⁷Lu‐DOTA‐3/F11 significantly slowed growth in C4–2 xenograft tumour model (<250 mm³ tumour volume in treated group at day 20 versus >1500 mm³ in the control group).	(Behe et al., 2011)
¹²⁵I	N/A	DCIBzL PSMA inhibitor	PC3 PIP (PSMA+) and PC3 flu (PSMA‐) and LnCap cells	Athymic nude mice	Uptake of ¹²⁵I‐DCIBzL was significantly higher in PSMA PC‐3 PIP (PSMA+) compared with PC‐3 flu (PSMA‐) cells.	(Kiess et al., 2015)
¹²⁵I	N/A	DCIBzL PSMA inhibitor	PC3 PIP (PSMA+) and PC3 flu (PSMA‐) and LnCap cells	Athymic nude mice	PC‐3 PIP tumours showed significantly (p = 0.002) delayed growth when treated with ¹²⁵I‐DCIBzL compared with PC‐3 flu tumours.	(Kiess et al., 2015)
¹³¹I	Adenovirus	hNIS	LnCap cells	BALB/c nude mice	A significantly higher uptake (p = 0.0075) of iodide was observed by xenograft tumours transfected with Ad.PSMApro‐hNIS vs. Ad.CMV (2846.03 ± 188.29 c.p.p.mg −1 vs. 9.19 ± 1.00 c.p.p.mg −1 respectively).	(Gao et al., 2014)
⁹⁰Y/¹⁷⁷Lu	N/A	PSMA antibody J591	N/A	Human clinical study	The single maximum tolerated dose (MTD) of ⁹⁰Y‐J591 and ¹⁷⁷Lu‐J5916. was 17.5 mCi/m2 and 70 mCi/m2.	(Vallabhajosula et al., 2005)
⁹⁰Y/¹⁷⁷Lu	N/A	PSMA antibody J591	N/A	Human clinical study	Several administrations over 4–6 months was well tolerated in patients where thrombocytopenia was manageable.	(Vallabhajosula et al., 2005)
¹⁷⁷Lu	N/A	PSMA antibody J591	N/A	Human clinical study	35 patients received ¹⁷⁷Lu‐J591. ¹⁷⁷Lu‐J591 was able to target all skeletal and soft tissue metastasis (determined by MRI).	(Bander et al., 2005)
¹⁷⁷Lu	N/A	PSMA antibody J591	N/A	Human clinical study	*There was no immunogenic response to J591. Four patients had a > 50% decline in PSMA with 16 showing PSA stabilization for median 60 days.	(Bander et al., 2005)
⁹⁰Y/¹³¹I	N/A	PSMA antibody J591	LnCap cells	BALB/c nude mice	15–90% reduction in LNCaP xenograft tumour volume following a single dose of either ⁹⁰Y‐J591 or ¹³¹I‐J591 was observed.	(Vallabhajosula et al., 2005)
⁹⁰Y/¹³¹I	N/A	PSMA antibody J591	LnCap cells	BALB/c nude mice	*An increase in survival time two to threefold compared with untreated controls was also observed.	(Vallabhajosula et al., 2005)