Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with <sup>211</sup>At-MX35-F(ab′)<sub>2</sub>: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival

Bäck, Tom; Chouin, Nicolas; Lindegren, Sture; Kahu, Helena; Jensen, Holger; Albertsson, Per; Palm, Stig

doi:10.2967/jnumed.116.178327

Cited by 18 publications

(15 citation statements)

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“…Accordingly, alpha camera imaging [22] at 3 hpi revealed a more uniform distribution of the 211 At-A11 minibody than was previously observed in an ovarian cancer xenograft model for the similarly sized 211 At-MX35-F(ab) 2 [22]. We have previously shown that complete eradication of s.c. macrotumors could be achieved by fractionated α-RIT for mean absorbed tumor doses > 10 Gy [21]. By adding a third fraction to the current study, i.e., increasing the highest tumor dose to 10.8 Gy, complete eradication might have been reached.…”

Section: Discussionmentioning

confidence: 82%

“…We have previously estimated the maximum tolerance dose (MTD) for the kidneys following systemic α-RIT with 211 At in mice [29] and reported a MTD of 10 Gy. In similar, we reported that the total absorbed dose needed for the eradication of macrotumors [21] was estimated to be 10 Gy, also. These numbers can be used as an example to compare the therapeutic window with or without NaClO 4 pre-treatment in the current study, i.e., anticipating the kidneys as the dose-limiting organ.…”

Section: Discussionmentioning

confidence: 82%

“…1), reaching a ratio of 5 at 23 hpi and close to 10 at 42 hpi. Included in the plot for comparison is the tumor-to-blood ratio of 211 At-MX35-F(ab') 2 , for which complete eradication of macrotumors was found by fractionated systemic α-RIT in an ovarian cancer model [21]. Alpha camera imaging [22] of the intratumoral activity distribution at 3 hpi showed that 211 At-A11 was well distributed throughout the macrotumors (Fig.…”

Section: Biodistribution and Uptake In Macrotumorsmentioning

confidence: 99%

“…1 The tumor-to-blood ratio (of %IA/g) of 211 At-A11 on s.c. PC3-PSCA macrotumors plotted versus time after injection. Included for comparison is the tumor-to-blood ratio of 211 At-MX35-F(ab') 2 , which was shown to be therapeutically efficient on macrotumors in previous studies of ovarian cancer [21] salivary glands and stomach, the dose decreased by 82% and 75%, respectively and for the thyroid and spleen by 57% and 53%. A decrease in dose was found also for the bladder and lungs, by 36% and 27%, respectively.…”

Section: Dosimetrymentioning

confidence: 99%

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Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

et al. 2020

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Purpose: Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic α-radioimmunotherapy (α-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the α-particle emitter 211 At-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases.Methods: PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of α-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9 MBq) and on i.t. microtumors (~100-200 μm; 0, 0.8 or 1.5 MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies.Results: Tumor targeting of 211 At-A11 was efficient and the effect on s.c. macrotumors was strong and dosedependent. At 6 weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5 MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4 MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5 MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 ± 0.003 mm 3 versus 3.79 ± 1.24 mm 3 (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted).

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 82%

Section: Biodistribution and Uptake In Macrotumorsmentioning

confidence: 99%

Section: Dosimetrymentioning

confidence: 99%

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Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

et al. 2020

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“…Instead we have, throughout this current work, used a threshold of 10 Gy to describe an eradicative dose. This choice is partly based on our previous work, which showed that cure of subcutaneous tumors from 211 At-MX35 irradiation was achieved at 10 Gy (18). Although this dose carries large uncertainties when used for microtumors and single cells, we have chosen to use it to discuss how intraperitoneal 211 At radioimmunotherapy can be optimized.…”

Section: Discussionmentioning

confidence: 99%

Model of Intraperitoneal Targeted α-Particle Therapy Shows That Posttherapy Cold-Antibody Boost Enhances Microtumor Radiation Dose and Treatable Tumor Sizes

et al. 2017

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Intraperitoneally administered radiolabeled monoclonal antibodies (mAbs) have been tested in several clinical trials, often with promising results, but have never proven curative. We have previously presented simulations of clinically relevant amounts of intraperitonealY-mAbs for treatment of minimal disease and shown that such treatments are unlikely to eradicate microtumors. Our previous model simulated the kinetics of intraperitoneally infused radiolabeled mAbs in humans and showed the benefit of instead using α-emitters such as At. In the current work, we introduce penetration of mAbs into microtumors with radii of up to 400 μm. Calculations were performed using dynamic simulation software. To determine the radiation dose distribution in nonvascularized microtumors of various sizes after intraperitonealAt-radioimmunotherapy, we used an in-house-developed Monte Carlo program for microdosimetry. Our aim was to find methods that optimize the therapy for as wide a tumor size range as possible. Our results show that high-specific-activity radiolabeled mAbs that are bound to a tumor surface will penetrate slowly compared with the half-lives ofAt and shorter-lived radionuclides. The inner-core cells of tumors with radii exceeding 100 μm may therefore not be sufficiently irradiated. For lower specific activities, the penetration rate and dose distribution will be more favorable for such tumors, but the dose to smaller microtumors and single cells will be low. Our calculations show that the addition of a boost with unlabeled mAb 1-5 h after therapy results in sufficient absorbed doses both to single cells and throughout microtumors up to approximately 300 μm in radius. This finding should also hold for other high-affinity mAbs and short-lived α-emitters.

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Radiotherapeutic Applications

Hasegawa¹,

Kawashima²,

Yagi³

et al. 2019

Handbook of in Vivo Chemistry in Mice

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Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with ²¹¹At-MX35-F(ab′)₂: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival

Cited by 18 publications

References 31 publications

Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

Model of Intraperitoneal Targeted α-Particle Therapy Shows That Posttherapy Cold-Antibody Boost Enhances Microtumor Radiation Dose and Treatable Tumor Sizes

Radiotherapeutic Applications

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Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with 211At-MX35-F(ab′)2: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival

Cited by 18 publications

References 31 publications

Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

Model of Intraperitoneal Targeted α-Particle Therapy Shows That Posttherapy Cold-Antibody Boost Enhances Microtumor Radiation Dose and Treatable Tumor Sizes

Radiotherapeutic Applications

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Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with ²¹¹At-MX35-F(ab′)₂: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival