| 11. |
- Garkavij, Michael, et al.
(författare)
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Improving radioimmonotargeting of tumors. Variation in the amount of L6 MAb administered, combined with an immunoadsorption system (ECIA)
- 1993
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 32:7-8, s. 853-859
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Tidskriftsartikel (refereegranskat)abstract
- Extracorporeal immunoadsorption (ECIA) is a new method for the selective removal of circulating radiolabeled monoclonal antibodies (MAb) from plasma to increase the uptake in tumor versus normal tissues (T/N-ratio). To ascertain whether the amount of MAb affects T/N ratios immediately and 24 h after ECIA, we used a rat model with two tumor sites--one intramuscular (im) and one below the subrenal capsule (SR). Extracorporeal immunoadsorption was done with an avidin-agarose column after injection of 125I-labeled biotinylated L6 MAb. The animals received 10, 50 or 250 micrograms of L6 only (controls), or followed by ECIA. The efficacy of the procedure in removing plasma activity was 80-95%. For both tumor sites, the highest T/N-ratios were obtained with 10 micrograms L6. All T/N-ratios significantly improved for SR tumors by a factor ranging from 3.2 (lung) to 12.6 (bone marrow). The T/N-ratios were still elevated 24 h after ECIA. Injection of larger amounts of MAb, probably causing a higher degree of tumor saturation, will not necessarily improve the T/N ratio after ECIA.
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| 12. |
- Garkavij, Michael
(författare)
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Improving radioimmunotargeting of tumors : the impact of extracorporeal immunoadsorption and preload in rats
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In radioimmunotherapy of tumors, uptake of the monoclonal antibody (MAb) used is often too low in relation to its uptake in normal tissues. The purpose of these studies was to improve experimental tumor radioimmunotargeting with (a) extracorporeal immunoadsorption (ECIA), where excess of radiolabeled MAbs circulating in blood is removed, (b) or by preload with unlabeled MAb prior to injection of radiolabeled MAb, (c) or by a combination of these. ECIA based on the avidin-biotin concept enables direct adsorption of radiolabeled and biotinylated MAb from blood and increases the tumor-to-normal tissue (T/N) uptake ratio by reducing background radioactivity in radiosensitive organs. 267 rats (athymic or Brown Norwegian) grafted with human adenocarcinoma or rat colon adenocarcinoma tumors intramuscularly, and beneath the kidney or liver capsule were included in the studies. Of these rats, 82 were subjected to ECIA. Two radioiodinated and biotinylated MAbs, murine L6 or chimeric BR96, were used and evaluated. (I) Using 50 µg dosage of L6, ECIA reduced whole body and plasma activity as well as improved the detectability of subrenal capsule tumors. T/N uptake ratios were increased on average 3 times. (II) The efficacy of ECIA in removing different injected amounts of L6 from plasma was similar. The highest T/N ratios persisting 24h after start of the ECIA were obtained by using 10 µg of 125I-L6-biotin. (III) The efficacy of preload in enhancing tumor uptake and simultaneously decreasing uptake in normal tissues was obtained with 250µg of 125I-L6 preceded by a preload of 50µg unlabeled L6 only. (IV) The effects on radioimmunotargeting of preload and ECIA in combination were synergistic and improved T/N uptake ratios up to 17 times. (V) As compared with ECIA, a new method of whole blood immunoadsorption (WBIA) was technically easier to perform, safer and more reliable, but of approx. comparable efficiency. (VI) WBIA was even applicable on the internalizing and highly tumor selective 125I-BR96-biotin MAb, resulting in manifestly improved T/N ratios.
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| 13. |
- Garkavij, Michael, et al.
(författare)
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Improving radioimmunotargeting of tumors: the impact of preloading unlabeled L6 monoclonal antibody on the biodistribution of 125I-L6 in rats
- 1994
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Ingår i: Journal of nuclear biology and medicine (Turin, Italy : 1991). - 0368-3249. ; 38:4, s. 594-600
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Tidskriftsartikel (refereegranskat)abstract
- In the radioimmunotherapy of malignancies the uptake of monoclonal antibodies (MoAb) is commonly low in tumors compared with normal tissue. Several methods have been suggested to increase the tumor-to-normal tissue (T/N) ratio. In this study we have investigated the biodistribution of different amounts of 125I-L6-biotin MoAb in combination with a preload of unlabeled L6 MoAb. Nude rats were injected with 50 micrograms or 250 micrograms of unlabeled L6 24 hours prior to the injection of 10 micrograms, 50 micrograms or 250 micrograms of 125I-L6, antipancarcinoma MoAb. Dissections were performed 24 hours after the injection of radiolabeled MoAb. The maximal enhancement of tumor uptake with simultaneously decreased uptake in normal tissues was with 250 micrograms of 125I-L6 preceded by a preload of 50 micrograms unlabeled L6. Mean T/N ratios were improved by a factor of 2.9 for bone marrow, 3.4 for liver, 3.7 for lungs and 2.3 for kidneys as compared with the corresponding controls. This study demonstrated that preinjection of optimal amounts of unlabeled L6 MoAb may increase the uptake of 125I-L6 by tumor and improve the T/N ratios. Based on present data, preloading with unlabeled MoAb should be considered in future clinical studies with immunoconjugates to improve the radioimmunotargeting of tumors. It is essential to titrate an appropriate amount of the preload, thus avoiding possible tumor antigen saturation of unlabeled MoAbs but simultaneously decreasing the uptake of subsequently injected radiolabeled MoAb in normal tissues.
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| 14. |
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| 15. |
- Nilsson, S., et al.
(författare)
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Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study
- 2007
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Ingår i: Lancet Oncol. - 1470-2045 .- 1474-5488. ; 8:7, s. 587-594
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The alpha-emitter radium-223 ((223)Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed to study mature outcomes from a randomised, multicentre, phase II study of (223)Ra. METHODS: Patients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of (223)Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. All tests were done at a 5% significance level, based on intention to treat. FINDINGS: Median relative change in bone-ALP during treatment was -65.6% (95% CI -69.5 to -57.7) and 9.3% (3.8-60.9) in the (223)Ra group and placebo groups, respectively (p<0.0001, Wilcoxon ranked-sums test). Hazard ratio for time to first SRE, adjusted for baseline covariates, was 1.75 (0.96-3.19, p=0.065, Cox regression). Haematological toxic effects did not differ significantly between two groups. No patient discontinued (223)Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16-39) versus 8 weeks (4-12; p=0.048) for (223)Ra versus placebo, respectively. Median overall survival was 65.3 weeks (48.7-infinity) for (223)Ra and 46.4 weeks (32.1-77.4) for placebo (p=0.066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2.12 (1.13-3.98, p=0.020, Cox regression). INTERPRETATION: (223)Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study (223)Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of (223)Ra could also potentially be used for treating skeletal metastasis from other primary cancers.
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| 16. |
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| 17. |
- Strand, Sven-Erik, et al.
(författare)
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A general extracorporeal immunoadsorption method to increase tumor-to-tissue ratio
- 1994
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Ingår i: Cancer. - 1097-0142. ; 73:3 Suppl, s. 1033-1037
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Tidskriftsartikel (refereegranskat)abstract
- The idea of applying extracorporeal immunoadsorption (ECIA) in radioimmunodiagnosis and radioimmunotherapy has been proposed previously. The authors here report on the development of new concept using a general method for ECIA based on biotinylated MoAb adsorbed on an avidin column. Athymic rats heterotransplanted with either human melanomas or human lung carcinoma were injected with iodine-125-labeled biotinylated 96.5 or L6 MoAb, respectively. At 24 or 48 hours after the injection, ECIA was performed by pumping blood through a hollow-fiber plasma filter. The separated plasma then was passed through an absorbent (avidin-agarose) column. The whole ECIA procedure lasted for 3 hours. By this ECIA method, the tumor-to-normal tissue ratios were increased in various tissues (i.e., radiosensitive and blood rich organs) by a factor of four to five.
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| 18. |
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| 19. |
- Toporski, Jacek, et al.
(författare)
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High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma.
- 2009
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Ingår i: Biology of Blood and Marrow Transplantation. - : Elsevier BV. - 1083-8791. ; 15:9, s. 1077-1085
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the feasibility and efficacy of using high-dose iodine-131-metaiodobenzylguanidine ((131)I-MIBG) followed by reduced-intensity conditioning (RIC) and transplantation of T cell-depleted haploidentical peripheral blood stem cells (designated haplo-SCT) to treat relapsing/refractory neuroblastoma (RRNB). Five RRNB patients were enrolled: 4 with relapse (3 after autologous SCT) and 1 with induction therapy failure. The preparative regimen included high-dose (131)I-MIBG on day -20, followed by fludarabine (Flu), thiotepa, and melphalan (Mel) from day -8 to -1. Granulocyte-colony stimulating factor (G-CSF)-mobilized, T cell-depleted haploidentical paternal stem cells were infused on day 0 together with cultured donor mesenchymal stem cells. A single dose of rituximab was given on day +1. After cessation of short immunosuppression (mycophenolate, OKT3), 4 children received donor lymphocyte infusion (DLI). (131)I-MIBG infusion and RIC were well tolerated. All patients engrafted. No primary acute graft-versus-host disease (aGVHD) was observed. Four children developed aGVHD after DLI and were successfully treated. Analysis of immunologic recovery showed fast reappearance of potentially immunocompetent natural killer (NK) and T cells, which might have acted as effector cells responsible for the graft-versus-tumor (GVT) effect. Two children are alive and well, with no evidence of disease 40 and 42 months after transplantation. One patient experienced late progression with new bone lesions (sternum) 38 months after haplo-SCT, and is being treated with local irradiation and reinstituted DLI. One patient rejected the graft, was rescued with autologous backup, and died of progressive disease 5 months after transplantation. Another child relapsed 7 months after transplantation and died 5 months later. High-dose (131)I-MIBG followed by RIC and haplo-SCT for RRNB is feasible and promising, because 2 of 5 children on that regimen achieved long-lasting remission. Further studies are needed to evaluate targeted therapy and immune-mediated tumor control in high-risk neuroblastoma.
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| 20. |
- Wang, Zhongmin, et al.
(författare)
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Application of extracorporeal immunoadsorption to reduce circulating blood radioactivity after intraperitoneal administration of indium-111-HMFG1-biotin.
- 2002
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Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 94:4 Suppl, s. 1287-1292
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Extracorporeal immunoadsorption (ECAT) is a method of reducing activity in radiosensitive organs by removing excess monoclonal antibodies (MAbs) from the blood. Previously, the authors experimentally evaluated ECAT based on the avidin-biotin concept after intravenous administration of radioimmunoconjugates. The aim of the current study was to determine whether ECAT could be used to reduce activity after intraperitoneal (i.p.) administration of indium-111((111)In)-HMFG1-biotin in rats, and to compare the pharmacokinetics of (111)In-HMFG1 with or without attached biotin after i.p. injection. METHODS: HMFG1, a murine immunoglobulin G(1) MAb that recognizes an epitope on the polymorphic epithelial mucin (PEM) antigen, was labeled with (111)In and then biotinylated. ECAT was explored from unseparated blood using an avidin-agarose adsorption column. Thirty rats were used as controls and 13 underwent ECAT. The whole-body (WB), blood, and organ activity were monitored. RESULTS: The binding capacity of (111)In-HMFG1-biotin to avidin was high. Biotinylation did not enhance the excretion of HMFG1. When ECAT was employed, the WB and blood radioactivity were reduced by 35-40% (P < 0.05) and 75--86% (P < 0.01), respectively. After the completion of ECAT, the activity uptake in organs was significantly decreased. CONCLUSIONS: ECAT was successfully applied after i.p. injection of the (111)In-HMFG-biotin MAb to reduce the radioactivity in the WB, blood, and radiosensitive organs. Due to redistribution of the radiolabeled MAbs during and after the completion of ECAT, the adsorption may have been prolonged or repeated. Biotinylation did not significantly change the biodistribution of the (111)In-HMFG1 in rats after intraperitoneal injection.
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