Analysis of Patient Survival in a Phase I Trial of Systemic Targeted α-Therapy for Metastatic Melanoma

Allen, Barry J.; Singla, Apresh; Rizvi, Syed Monem; Graham, Peter; Bruchertseifer, Frank; Apostolidis, Christos; Morgenstern, Alfred

doi:10.2217/imt.11.97

Cited by 84 publications

(59 citation statements)

References 20 publications

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“…To date, clinical alpha particle RIT has been investigated in patients with hematological malignancies [54], [55], ovarian [56], melanoma [57] or brain tumors [58]. Our study gives preclinical rationale for the ongoing Phase I study (NCT01384253) as the toxicity was less than previously reported suggesting the potential for dose escalation with acceptable toxicity and a higher therapeutic efficacy.…”

Section: Discussionmentioning

confidence: 80%

Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 212Pb

et al. 2013

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Background and PurposeWe assessed the contribution of antibody internalization in the efficacy and toxicity of intraperitoneal α-radioimmunotherapy (RIT) of small volume carcinomatosis using 212Pb-labeled monoclonal antibodies (mAbs) that target HER2 (internalizing) or CEA (non-internalizing) receptors.Materials and MethodsAthymic nude mice bearing 2–3 mm intraperitoneal tumor xenografts were intraperitoneally injected with similar activities (370, 740 and 1480 kBq; 37 MBq/mg) of 212Pb-labeled 35A7 (anti-CEA), trastuzumab (anti-HER2) or PX (non-specific) mAbs, or with equivalent amounts of unlabeled mAbs, or with NaCl. Tumor volume was monitored by bioluminescence and survival was reported. Hematologic toxicity and body weight were assessed. Biodistribution of 212Pb-labeled mAbs and absorbed dose-effect relationships using MIRD formalism were established.ResultsTransient hematological toxicity, as revealed by white blood cells and platelets numbering, was reported in mice treated with the highest activities of 212Pb-labeled mAbs. The median survival (MS) was significantly higher in mice injected with 1.48 MBq of 212Pb-35A7 (non-internalizing mAbs) (MS = 94 days) than in animals treated with the same activity of 212Pb-PX mAbs or with NaCl (MS = 18 days). MS was even not reached after 130 days when follow-up was discontinued in mice treated with 1.48 MBq of 212Pb-trastuzumab. The later efficacy was unexpected since final absorbed dose resulting from injection of 1.48 MBq, was higher for 212Pb-35A7 (35.5 Gy) than for 212Pb-trastuzumab (27.6 Gy). These results also highlight the lack of absorbed dose-effect relationship when mean absorbed dose was calculated using MIRD formalism and the requirement to perform small-scale dosimetry.ConclusionsThese data indicate that it might be an advantage of using internalizing anti-HER2 compared with non-internalizing anti-CEA 212Pb-labeled mAbs in the therapy of small volume xenograft tumors. They support clinical investigations of 212Pb-mAbs RIT as an adjuvant treatment after cytoreductive surgery in patients with peritoneal carcinomatosis.

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Section: Discussionmentioning

confidence: 80%

Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 212Pb

et al. 2013

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“…Targeted alpha particle emitters are currently under clinical investigations for leukemia (32) ovarian cancer (33), malignant melanoma (34) and glioblastoma (35) because of their high potency. The recent clinical success of Radium-223 (Alpharadin) in castration-resistant prostate cancer with bone metastases (36) supports further development of alpha particle emitters and highlights the importance of a unique biological mechanism in the highly specific accumulation of targeted radioisotopes.…”

Section: Discussionmentioning

confidence: 99%

Targeting Aberrant DNA Double-Strand Break Repair in Triple-Negative Breast Cancer with Alpha-Particle Emitter Radiolabeled Anti-EGFR Antibody

Song

Hedayati²,

Hobbs

et al. 2013

Molecular Cancer Therapeutics

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The higher potential efficacy of alpha-particle radiopharmaceutical therapy lies in the 3 to 8-fold greater biological effectiveness (RBE) of alpha particles relative to photon or beta-particle radiation. This greater RBE, however, also applies to normal tissue, thereby reducing the potential advantage of high RBE. Since alpha particles typically cause DNA double strand breaks (DSBs), targeting tumors that are defective in DSB repair effectively increases the RBE, yielding a secondary, RBE-based differentiation between tumor and normal tissue that is complementary to conventional, receptor-mediated tumor targeting. In some triple negative breast cancers (TNBC, ER−/PR−/HER-2−), germline mutation in BRCA-1, a key gene in homologous recombination (HR) DSB repair, predisposes patients to early onset of breast cancer. These patients have few treatment options once the cancer has metastasized. In this study, we investigated the efficacy of alpha particle emitter, 213Bi labeled anti-EGFR antibody, Cetuximab, in BRCA-1 defective TNBC. 213Bi-Cetuximab was found to be significantly more effective in the BRCA-1 mutated TNBC cell line HCC1937 than BRCA-1 competent TNBC cell MDA-MB-231. siRNA knockdown of BRCA-1 or DNA-PKcs, a key gene in non-homologous end joining (NHEJ) DSB repair pathway, also sensitized TNBC cells to 213Bi-Cetuximab. Furthermore, the small molecule inhibitor of DNA-PKcs, NU7441, sensitized BRCA-1 competent TNBC cells to alpha particle radiation. Immunofluorescent staining of γH2AX foci and comet assay confirmed that enhanced RBE is caused by impaired DSB repair. These data offer a novel strategy for enhancing conventional receptor-mediated targeting with an additional, potentially synergistic radiobiological targeting that could be applied to TNBC.

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“…The range of α-particles is rather short in tissue in comparison to beta particles (50–80 µm vs. 0.8–12 mm); they have a much higher linear energy transfer (100 keV/µm vs. 0.2 keV/µm) [129]. Currently, there are clinical trials for different types of cancer with targeted high potent α-emitters [132,133,134]. In an in vitro study 213 Bi-labeled CHX-A′′DTPA-cetuximab showed effective double-strand breaks on different human breast cancer cells, but for an approach in patients the safety of targeted α-emitter-labeled radioconjugates has to be evaluated [135].…”

Section: Radiolabeled Cetuximabmentioning

confidence: 99%

Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy

et al. 2014

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The epidermal growth factor receptor (EGFR) has evolved over years into a main molecular target for the treatment of different cancer entities. In this regard, the anti-EGFR antibody cetuximab has been approved alone or in combination with: (a) chemotherapy for treatment of colorectal and head and neck squamous cell carcinoma and (b) with external radiotherapy for treatment of head and neck squamous cell carcinoma. The conjugation of radionuclides to cetuximab in combination with the specific targeting properties of this antibody might increase its therapeutic efficiency. This review article gives an overview of the preclinical studies that have been performed with radiolabeled cetuximab for imaging and/or treatment of different tumor models. A particularly promising approach seems to be the treatment with therapeutic radionuclide-labeled cetuximab in combination with external radiotherapy. Present data support an important impact of the tumor micromilieu on treatment response that needs to be further validated in patients. Another important challenge is the reduction of nonspecific uptake of the radioactive substance in metabolic organs like liver and radiosensitive organs like bone marrow and kidneys. Overall, the integration of diagnosis, treatment and monitoring as a theranostic approach appears to be a promising strategy for improvement of individualized cancer treatment.

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Analysis of Patient Survival in a Phase I Trial of Systemic Targeted α-Therapy for Metastatic Melanoma

Cited by 84 publications

References 20 publications

Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 212Pb

Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 212Pb

Targeting Aberrant DNA Double-Strand Break Repair in Triple-Negative Breast Cancer with Alpha-Particle Emitter Radiolabeled Anti-EGFR Antibody

Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy

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