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. 2020 Feb 19;12(2):481. doi: 10.3390/cancers12020481

Table 4.

In vivo studies performed using α and β RIT in PDAC.

Study Target RIC Therapies Assessed Survival Tumour Growth Tumour Uptake (% ID/g ± SD) Side Effects
A-RIT Studies
Kasten et al. [46] B7-H3 212Pb-376.96 RIT only Not investigated Significant inhibition of tumour growth at all RIT dose levels compared to untreated controls At 24 h:
14.0 ± 2.1 (RIT)
6.5 ± 0.9 (212Pb-control)		 Transient weight loss
Poty et al. [57] CA19-9 225Ac-5B1 PT-RIT Median survival (orthotopic tumours):
67.5 days (37 kBq PT-RIT)
60.0 days (37 kBq RIT only)
32 days (18.5 kBq PT-RIT)
46 days (18.5 kBq RIT only)
28.5 days (vehicle-only control)		 Not investigated At 4 h:
4.6 ± 3.3 (PT-RIT)
15.4 ± 3.5 (conventional RIT)
At 72 h: 29.6 ± 6.6 (PT-RIT)
31.1 ± 21.4 (conventional RIT)		 All RIT groups:
Transient weight loss, mild nephrotoxicity, transient haemotoxicity (more severe in conventional RIT group compared to PT-RIT group)
Conventional RIT: disseminated intravascular coagulation (2/10)
Jiao et al. [29] CENT1 213Bi-69-11 Comparison of 213Bi-69-11 and 177Lu-69-11 Not investigated 3.7–7.4 MBq of 213Bi-69-11: Significant reduction in tumour growth rate compared to controls Not investigated Transient haemotoxicity
Milenic et al. [58] HER2 213Bi-Herceptin RIT only Median survival:
15 days (untreated controls)2
2 days (213Bi-control)
26 days (18.5 MBq RIT)
28 days (37 MBq RIT)
26 days (74 MBq RIT)		 Not investigated in PDAC xenografts 111In-Herceptin
24 h: 19.47 ± 3.04
48 h: 31.00 ± 8.92
72 h: 34.00 ± 10.15
120 h: 29.89 ± 3.96
168 h: 15.34 ± 5.14 		Increasing weight loss with dose
Bryan et al. [59] ssDNA and RNA 213Bi-chTNT3 RIT compared to gemcitabine and cisplatin Survival:
100% at day 65 (RIT, cold chTNT3 and untreated)
40% at day 65 (gemcitabine)
0% at day 15 (cisplatin)		 Significant reduction in tumour size for RIT and gemcitabine compared to controls Ratio of sum of pixels in tumour region to sum of pixels in internal organs:
1 h: 0.18
2 h: 0.22
24 h: 0.72
48 h: 0.68		 No RIT-related side effects
Qu et al. [37] uPA/uPAR 213Bi-PAI2 Comparing local and systemic RIT injections Local injection
Time to end point:
35 days (cold PAI2)
>84 days (≥111 MBq/kg RIT)
Systemic injection
Time to end point:
35 days (cold PAI2)
50 days (111 MBq/kg RIT)
66 days (222 MBq/kg RIT)		 Local injection
Tumour growth in:
0/5 tumours (222 MBq/kg RIT)
3/5 tumours (111 MBq/kg RIT)
5/5 tumours (cold PAI2)
Systemic injection
Tumour growth in:
3/5 tumours (222 MBq/kg RIT)
5/5 tumours (111 MBq/kg RIT)
5/5 tumours (cold PAI2)		 Not investigated Not reported
Song et al. [60] uPA/uPAR 213Bi-PAI2 RIT only Time to end point:
175 days (470 MBq/kg RIT)
162 days (590 MBq/kg RIT)
Did not reach end-point (350 MBq/kg RIT and control groups)		 Not investigated Not investigated Body weight loss with increasing dose. Decline in renal function.
Qu et al. [47] MUC1 213Bi-C595 Comparing local and systemic RIT injections Local injection
Time to end point:
42 ± 7 days (cold C595)
74 ± 3 days (213Bi-control)
77 days (1.85 MBq RIT)
>112 days (3.7–7.4 MBq RIT)
Systemic injection
42 days (cold C595)
56 days (213Bi-control)
>112 days (≥ 111 MBq/kg RIT)		 Local injection
Tumour growth in:
0/5 tumours (3.7–7.4 MBq RIT)
1/5 tumours (1.85 MBq RIT)
5/5 tumours (cold C595 and 213Bi-control)
Systemic injection
Tumour growth in:
0/5 tumours (≥222 MBq/kg RIT)
2/5 tumours (111 MBq/kg RIT)
5/5 tumours (cold C595 and 213Bi-control)		 Not investigated Transient weight loss
B-RIT Studies
Jiao et al. [29] CENT1 177Lu-69-11 Comparison of 213Bi-69-11 and 177Lu-69-11 Not investigated 177Lu-69-11: No significant reduction in tumour growth compared to control treatments Clear localisation of RIC in tumour at 24 h Transient haemotoxicity
Houghton et al. [61] CA19-9 177Lu-DOTA-PEG7-Tz PT-RIT using 5B1-TCO Not investigated Tumour doubling time was significantly increased in 44.4 MBq PT-RIT compared to controls and 14.8 MBq PT-RIT.
Tumour volume was reduced in 44.4 and 29.6 MBq PT-RIT compared to controls.		 At 120 h:
16.8 ± 3.87 (PT-RIT)		 No side effects observed
Sharkey et al. [55] MUC1 90Y-hPAM4 Combined RIT and antibody-drug conjugate (ADC) (hRS7–SN-38) Median time to progression:
4.3 weeks (untreated)
9.75 weeks (ADC only)
13 weeks (2.78 MBq RIT only)
>21 weeks (Combined therapy and 4.8 MBq RIT only)		 Tumour-free mice at 21 weeks:
0/9 (untreated control)
1/10 (ADC only)
1/10 (2.8 MBq RIT only)
5/10 (4.8 MBq RIT only)
4/10 (Combined therapy using 2.8 MBq RIT)
9/10 (Combined therapy using 4.8MBq RIT)		 At 48 h:
48.4 ± 16.4 		Transient weight loss
Aung et al. [62] Integrin α6β4 90Y-ITGA6B4 Single and double RIT cycles Not calculated—all mice euthanised at day 27 Growth rates significantly reduced in single and double RIT cycles compared to controls Not investigated Increasing haemotoxicity with RIT activity
Aung et al. [50] Integrin α6β4 90Y-ITGA6B4 Combined RIT and PI3K/mTOR inhibitor (BEZ235) Not investigated Compared to controls, tumour growth significantly delayed for:
58 days (2.8 MBq RIT only)
23 days (BEZ235 only)
Compared to RIT only, tumour growth significantly delayed for 27 days for combined therapy
Compared to BEZ235 only, tumour growth significantly delayed for 41 days for combined therapy.		 Not investigated No side effects observed
Aghevlian et al. [63] EGFR 177Lu-panitumumab RIT only Not investigated Not investigated At 72 h:
6.9 ± 1.3 (111In-MCP-panitumumab)
6.6 ± 3.3 (111In-DOTA-panitumumab)
1.9 ± 0.3 (111In-DOTA-control)
5.4 ± 0.3 (111In-MCP-control)
In 100-fold excess of panitumumab:
0.02 ± 0.00 (111In-MCP-panitumumab)
0.06 ± 0.02 (111In-DOTA-panitumumab)		 Not investigated
Aghevlian et al. [49] EGFR 177Lu-panitumumab RIT only Not investigated Tumour growth index at 33 days (mean ± SEM):
2.5 ± 0.3 (RIT)
4.0 ± 0.7 (Control RIC)
6.1 ± 1.1 (cold panitumumab)
5.8 ± 0.5 (untreated)		 Absorbed tumour dose for 6 Mbq of RIC:
12.33 ± 0.86 Gy		 No significant effects over 14 days
Al-Ejeh et al. [6] EGFR 177Lu-anti EGFR Combined RIT, gemcitabine and Chk1 inhibition (triple therapy) Not investigated Tumour growth rate of all triple therapy dose combinations was significantly less than combined gemcitabine and Chk1 inhibition.
Complete tumour regression in triple therapy.		 Not investigated Weight loss with high doses of gemcitabine or RIT
Sugyo et al. [48] CD147 90Y-059-053 Combined RIT and gemcitabine Survival at day 42:
0% (untreated, cold CD147, 0.925 and 1.85 MBq RIT)
0% and 20% (3.7 MBq RIT in two experiments)
40% (Combined therapy)		 Significant suppression of tumour growth in 3.7 MBq RIT and combined therapy groups compared to untreated and gemcitabine only groups 111In-059-053
30 min: 1.04 ± 0.16
24 h: 9.23 ± 0.67
48 h: 16.13 ± 0.92
96 h: 16.78 ± 2.61
168 h: 14.98 ± 1.63 		Weight loss, diarrhea and decreasing activity with multiple cycles
Sabbah et al. [30] Ferritin 90Y and 111In-labelled
Bz-DTPA-AMB8LK, Bz-CHX-AU-DTPA-AMB8LK and Bz-DOTA-AMB8LK		 RIT only—comparing different conjugates Not investigated Not investigated 90Y-DTPA-AMB8LK:
24 h: 14.0 ± 7.5
48 h: 18.6 ± 1.9
120 h: 16.2 ± 2.9
90Y-DOTA-AMB8LK:
24 h: 14.1 ± 1.2
48 h: 12.9 ± 2.3
120 h: 11.2 ± 4.5 		Not investigated
Vervoort et al. [32] Integrin avß5 131I-14C5 RIT only Not investigated Not investigated 131I-14C5
1 h: 3.63 ± 0.50
24 h: 11.22 ± 3.31
48 h: 12.16 ± 1.03
72 h: 8.45 ± 0.57
168 h: 6.91 ± 1.84 		Not investigated
Al-Ejeh et al. [64] Intracellular La ribonucleoprotein 90Y-DOTA-DAB4 Combination RIT, gemcitabine and cisplatin Median survival
31 days (2.40 MBq RIT only)
47 days (Combined therapy)
24 days (untreated control)		 Tumour doubling time (days ± SEM):
4.44 ± 0.02 (control)
5.87 ± 0.04 (RIT only)
4.88 ± 0.01 (chemotherapy only)
8.53 ± 0.02 (combined therapy)		 Not investigated in PDAC model Not investigated in PDAC model
Sugyo et al. [51] Transferrin 90Y-TSP-A01 RIT only Not investigated BxPC-3 tumours: 1.85 and 3.7 MBq RIT significantly delayed tumour growth compared to unlabelled A01. No significant difference in tumour volume between 0.74 MBq RIT and unlabelled A01.
MIAPaCa-2: Tumour volumes in 1.85 MBq and 3.7 MBq RIT groups were reduced to 20%. Complete resolution of tumours treated with 3.7 MBq RIT by 6 weeks. 		Peak 111In-TSP-A01 uptake:
37.5 ± 5.3 at 24 h (MIAPaCa-2)
27.0 ± 10.7 at 96 h (BxPC-3)		 Transient decrease in body weight
Baranowska-Kortylewicz et al. [65] PDGFR 131I-CC49 Combined RIT and PDGFR inhibitor (imatinib) Not investigated Tumour doubling time (days):
12.86 ± 0.19 (RIT only)
26.06 ± 1.47 (combined therapy)
13.03 ± 0.27 (imatinib only)
9.05 ± 0.05 (untreated control)		 At 120 h:
6.06 ± 1.76 (RIC only)
9.03 ± 1.59 (RIC and imatinib)		 No side effects
Cardillo et al. [66] MUC1 131I-PAM4 and 90Y-PAM4 Comparing RICs as stand-alone treatments Median survival:
6 weeks (untreated)
13 weeks (13 MBq 131I RIT)
12 weeks (19 MBq 131I RIT)
17.5 weeks (26 MBq 131I RIT)
16 weeks (4.8 MBq 90Y RIT)
>26 weeks (≥6.5 MBq 90Y RIT)		 Mean size of tumours at nadir (cm3):
N/A (untreated and ≤19 MBq 131I RIT as tumours never regressed)
0.61 ± 0.24 (26 MBq 131I RIT at 7 weeks)
0.78 ± 0.61 (4.8 MBq 90Y RIT at 6 weeks)
0.33 ± 0.40 (6.5 MBq 90Y RIT at 7 weeks)
0.10 ± 0.07 (8.1 MBq 90Y RIT at 9 weeks)
0.19 ± 0.13 (9.6 MBq 90Y RIT at 10 weeks)		 Radiation dose estimates to tumour (cGy):
8559 (26 MBq 131I RIT)
8068 (9.6 MBq 90Y RIT)		 Weight loss
Gold et al. [67] MUC1 90Y-PAM4 Single RIT Not investigated Not investigated 96 h: 39.5 ± 16.4 Not investigated
Cardillo et al. [68] MUC1 131I-PAM4 Combined RIT and gemcitabine Median survival:
6 weeks (3.7 MBq RIT only)
10 weeks (combined therapy using 3.7 MBq RIT)
9 weeks (combined therapy using 3.7 MBq 131I control)
13 weeks (7.4 MBq RIT only)
13 weeks (combined therapy using 7.4 MBq RIT)
10 weeks (combined therapy using 7.4 MBq control RIC)
6 weeks (untreated controls)
5 weeks (gemcitabine only)		 Normalised tumour growth at week 4:
3.91 ± 2.54 (3.7 MBq RIT only)
1.69 ± 1.26 (combined therapy using 3.7 MBq RIT)
1.45 ± 1.05 (combined therapy using 3.7MBq 131I control)
1.58 ± 0.84 (7.4 MBq RIT only)
1.13 ± 0.50 (combined therapy using 7.4 MBq RIT)
1.92 ± 1.02 (combined therapy using 7.4 MBq control RIC)
4.16 ± 0.89 (untreated control)
4.35 ± 1.80 (gemcitabine only)		 131I-PAM4:
24 h: 12.08 ± 6.85
72 h: 11.08 ± 5.56
168 h: 8.04 ± 6.13
336 h: 4.00 ± 2.80
131I-PAM4 and gemcitabine:
24 h: 12.21 ± 5.73
72 h: 14.29 ± 7.31
168 h: 8.39 ± 6.50
336 h: 2.52 ± 2.30		 Weight loss
Gold et al. [69] MUC1 90Y-PAM4 Combined RIT and gemcitabine Median survival
16 weeks (RIT only)
24 weeks (combined therapy)
11 weeks (combined therapy with 90Y control)
8 weeks (90Y control only)
10 weeks (gemcitabine only)
8.5 weeks (untreated controls)		 Tumour response
Week 10:
1/9 PR (RIT only)
1/9 CR, 3/9 PR, 2/9 SD (combined therapy)
Disease progression in all other groups
Week 26:
4/9 CR (combined therapy)		 111In-cPAM4:
24 h: 18.65 ± 2.93
96 h: 26.93 ± 11.81
168 h: 18.05 ± 11.02
111In-cPAM4 and gemcitabine:
24 h: 21.79 ± 4.55
96 h: 36.70 ± 9.58
168 h: 25.47 ± 10.35		 Weight loss and transient reduction in white blood cell counts
Gold et al. [70] MUC1 90Y-PAM4 Combined RIT and gemcitabine Median survival
12 weeks (single cycle combined therapy)
9 weeks (single RIT only)
7 weeks (single cycle combined 90Y control)
4 weeks (gemcitabine only) 6 weeks (untreated controls)
21 weeks (double cycle combined therapy)
16 weeks (double RIT only)
10 weeks (double cycle combined 90Y control)		 Tumour response:
1/13 PR, 8/13 SD (single cycle combined therapy)
7/12 SD (single RIT only)
1/8 PR (90Y control only)
1/10 CR (single cycle combined 90Y control therapy)
1/13 SD (double cycle 1.85 MBq 90Y control)
3/13 SD, 1/13 PR (double cycle combined 1.85 MBq 90Y control therapy)
3/12 SD, 4/12 PR (double cycle 3.7 MBq RIT)
4/12 SD, 7/12 PR (double cycle combined 3.7 MBq RIT)		 Not investigated Transient weight loss
Karacay et al. [56] MUC1 PT-RIT: 90Y-IMP-288
RIT only: 90Y-PAM4		 Combined TF10 PT-RIT and gemcitabine Time to progression
16.3 weeks (9.25 MBq PT-RIT)
5.4 week (untreated controls)
>30 weeks (18.5 MBq PT-RIT and 5.55 MBq 90Y RIT only)
4.8 weeks (9.25MBq PT-RIT)
18.1 weeks (combined PT-RIT and gemcitabine)		 Tumour-free mice at week 19:
8/10 (18.5 MBq PT-RIT)
3/10 (9.25 MBq PT-RIT)
8/9 (5.55 MBq RIT only)
0/10 (untreated controls)		 Not investigated Transient decrease in white blood cell counts, diarrhea (1/11). No nephrotoxicity observed.

RIC: radioimmunoconjugate, %ID/g: percentage of injected dose/gram, SD: standard deviation, PT: pre-targeted, CIT: chemoimmunotherapy, PI3K/mTOR: phosphatidylinositol-3-kinase/mammalian target of rapamycin, MCP: metal chelating polymer, SEM: standard error measurement, Chk1: checkpoint kinase 1, PR: partial response, SD: stable disease, CR: complete resolution.