Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma

Klein, Marc; Lotem, Michal; Peretz, Tamar; Zwas, S. Tzila; Mizrachi, S.; Liberman, Y.; Chisin, Roland; Schachter, Jacob; Ron, Idit; Iosilevsky, Galina; Kennedy, John A.; Revskaya, Ekaterina; Kater, A W de; Banaga, E.; Klutzaritz, Vicki; Friedmann, Nadav; Galun, Eithan; DeNardo, Gerald L.; DeNardo, Sally J.; Casadevall, Arturo; Dadachova, Ekaterina; Thornton, George B.

doi:10.1155/2013/828329

Cited by 41 publications

(36 citation statements)

References 12 publications

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“…In support of these results, we have already shown that a high dose of Listeria at or 188 Re is less toxic in humans than chemotherapy (11)(12)(13). Currently, other Listeria constructs are available with reduced pathogenicity and used for different approaches.…”

Section: Discussionsupporting

confidence: 53%

“…Using medical internal radiation dose formalism, we have estimated that the dose delivered to the tumor by RL was ∼30 Gy, which is within a tumoricidal range for internal radionuclide therapy (5). (11)(12)(13), the combination of Listeria at and radioactivity has never been tested for its safety in vivo. Therefore, we performed various experiments aimed at testing RL safety, such as biodistribution of RL, free 188 Re, and Listeria at ; pathology; and liver functions.…”

Section: Listeriamentioning

confidence: 99%

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Nontoxic radioactive Listeria ^at is a highly effective therapy against metastatic pancreatic cancer

Quispe-Tintaya¹,

Chandra²,

Jahangir³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

145

172

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No significant improvement in therapy of pancreatic cancer has been reported over the last 25 y, underscoring the urgent need for new alternative therapies. Here, we coupled a radioisotope, 188 Rhenium, to an attenuated (at) live Listeria monocytogenes (Listeria at ) using Listeria-binding antibodies, thus creating a unique radioactive Listeria at (RL). We then demonstrated in a highly metastatic pancreatic mouse tumor model (Panc-02) that RL delivered radioactivity to the metastases and less abundantly to primary tumors in vivo, without harming normal cells. This result was possible because Listeria at was efficiently cleared by the immune system in normal tissues but not in the heavily immune-suppressed microenvironment of metastases and primary tumor. Multiple treatments with low doses of the RL resulted in a dramatic decrease in the number of metastases (∼90%) compared with control groups in the Panc-02 model. This is the first report of using live attenuated bacteria delivering a highly radioactive payload to the metastases, resulting in killing tumor cells in vivo without harming normal cells. The nontoxic RL treatment is attractive for clinical development as a therapy to prevent pancreatic cancer recurrence and metastases. P ancreatic ductal adenocarcinoma, synonymous to pancreatic cancer, is the fourth leading cause of cancer deaths. The socalled silent killer is characterized by its metastatic behavior before the primary tumor can be detected, resulting in a 5-y survival rate of only 4%. Current cancer treatments-i.e., surgery followed by radiation and/or chemotherapy-are ineffective, particularly against liver metastases. Gemcitabine and erlotinib, Food and Drug Administration-approved drugs for pancreatic cancer treatment, improve median survival by ∼6 mo in patients with advanced-stage disease (1-3), emphasizing the need for new alternative therapies for metastatic pancreatic cancer.For any anticancer approach to be effective, it needs to target metastases and/or remaining tumor cells after primary therapeutic intervention. Indeed, in most cases, cancer therapy is now highly effective in eradicating primary tumors through combinations of surgery, radiation, and adjuvant therapy. The reason that cancer remains such a formidable health problem is its capacity to recur in the form of widespread metastases, often with a fatal consequence. In a previous study, we found that a highly attenuated bacterium, Listeria monocytogenes (Listeria at ), which was originally used to deliver tumor-associated antigens into antigen-presenting cells, also infected tumor cells in vitro and in vivo (4). Although Listeria at was efficiently cleared by the immune system in the normal tissues within 3-5 d, immune suppression in the tumor microenvironment allowed these bacteria to accumulate in metastases and primary tumors and to kill tumor cells through high levels of reactive oxygen species (ROS) (4). Based on these results we hypothesized that Listeria at could be used to deliver anticancer agents, such as therapeutic ...

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Section: Discussionsupporting

confidence: 53%

Section: Listeriamentioning

confidence: 99%

Nontoxic radioactive Listeria ^at is a highly effective therapy against metastatic pancreatic cancer

Quispe-Tintaya¹,

Chandra²,

Jahangir³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

145

172

View full text Add to dashboard Cite

show abstract

“…However, preclinical and clinical studies have not determined the impact of RIT on stem cells. Encouraged by the promising results in a clinical trial with 188 Re-labeled anti-Melanin MAb 6D2 (IgM) in patients with metastatic melanomas, 53 Jandl et al evaluated the effect of 188 Re-6D2 on the stem cells in a preclinical xenograft model. 54 As compared to untreated controls, the 188 Re-6D2 treated animals had a fourfold decrease in tumor size.…”

Section: Targeting Stem Cells With Radiolabeled Antibodiesmentioning

confidence: 99%

Emerging Trends for Radioimmunotherapy in Solid Tumors

Jain

Gupta

Kaur

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and undesirable pharmacokinetics, however, have precluded the administration of radioimmunoconjugates at therapeutically relevant doses thereby limiting the clinical utility of RIT. In solid tumors, efficacy of RIT is further compromised by heterogeneities in blood flow, tumor stroma, expression of target antigens and radioresistance. As a result significant efforts have been invested toward developing strategies to overcome these impediments. Further, there is an emerging interest in exploiting shortrange, high energy a-particle emitting radionuclides for the eradication of minimal residual and micrometastatic disease. As a result several modalities for localized therapy and models of minimal disease have been developed for preclinical evaluation. This review provides a brief update on the recent efforts toward improving the efficacy of RIT for solid tumors, and development of RIT strategies for minimal disease associated with solid tumors. Further, some of promising approaches to improve tumor targeting, which showed promise in the past, but have now been ignored are also discussed.

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“…To test this hypothesis, we used data on biodistribution of 188 Re-labeled antibody to melanin in athymic melanoma xenograft-bearing mice (6,7).…”

mentioning

confidence: 99%

New Approaches for Modeling Radiopharmaceutical Pharmacokinetics Using Continuous Distributions of Rates

Shuryak

Dadachova

2015

J Nucl Med

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Radiopharmaceutical pharmacokinetics are usually approximated by sums of discrete first-order rates, using 3 or more parameters. We hypothesized that pharmacokinetic processes can be modeled even better by continuous probability distributions (CPD) of rates, using only 1-2 parameters. Methods: To test this hypothesis, we used biodistribution data for 188 Re-labeled melanin-specific antibody in blood, kidneys, liver, bone marrow, and lungs of melanoma xenograft-bearing mice. We used 3 discrete-rate models (monoexponential, monoexponential with constant, and biexponential) and 4 CPD models (stretched-exponential, modified stretched-exponential, simplified versions of stretched-exponential, and modified stretched-exponential). They were compared by sample-size-corrected Akaike information criterion. Total time integrals of radioactivity were computed for each model and averaged across all models. Results: The ratio of weights of evidence for CPD versus discrete-rate models was high for blood (12.2) and lungs (2.7), almost unity (0.99) for bone marrow, and slightly lower for kidneys (0.81) and liver (0.73). In all organs or tissues except lungs, model-averaged time integrals were 12.7%-54.0% higher than biexponential model estimates. Conclusion: Simple CPD models often outperform more complex discrete-rate models on pharmacokinetic data. Radioactivity time integrals are more robustly estimated by multimodel inference than using any single model. Phar macokinetics of radiopharmaceuticals (e.g., radioimmunotherapy agents) are assumed to follow first-order kinetics and are, therefore, approximated by the sum of discrete rates (1-3). However, the existence of first-order kinetics does not necessarily imply the existence of only a few discrete rates. Instead, complex decay patterns may result from a continuous probability distribution (CPD) of first-order rates (4,5). "Depending on the level of precision, a decay can be fitted with a sum of 2 or 3 exponentials with satisfactory x 2 values and weighted residuals despite the existence of an underlying distribution" (5).We hypothesized that pharmacokinetic processes can be modeled even better by CPDs of rates using only 1-2 parameters than by sums of discrete rates using 3 or more parameters. To test this hypothesis, we used data on biodistribution of 188 Re-labeled antibody to melanin in athymic melanoma xenograft-bearing mice (6,7).We used 7 models to fit the data. Three of them assumed discrete pharmacokinetic rates, and 4 assumed CPDs. We compared the performances of these models, and their predictions for the total time integral of radioactivity (which is needed for radiopharmaceutical dosimetry), using information theoretic methods. Our results provide new insight into modeling of radiopharmaceutical pharmacokinetics. MATERIALS AND METHODS DatasetsThe biodistribution studies analyzed here were published (6) and are described in the supplemental data (supplemental materials are available at http://jnm.snmjournals.org). Briefly, athymic mice (maintained in accordance wi...

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Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma

Cited by 41 publications

References 12 publications

Nontoxic radioactive Listeria ^at is a highly effective therapy against metastatic pancreatic cancer

Nontoxic radioactive Listeria ^at is a highly effective therapy against metastatic pancreatic cancer

Emerging Trends for Radioimmunotherapy in Solid Tumors

New Approaches for Modeling Radiopharmaceutical Pharmacokinetics Using Continuous Distributions of Rates

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Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma

Cited by 41 publications

References 12 publications

Nontoxic radioactive Listeria at is a highly effective therapy against metastatic pancreatic cancer

Nontoxic radioactive Listeria at is a highly effective therapy against metastatic pancreatic cancer

Emerging Trends for Radioimmunotherapy in Solid Tumors

New Approaches for Modeling Radiopharmaceutical Pharmacokinetics Using Continuous Distributions of Rates

Contact Info

Product

Resources

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Nontoxic radioactive Listeria ^at is a highly effective therapy against metastatic pancreatic cancer

Nontoxic radioactive Listeria ^at is a highly effective therapy against metastatic pancreatic cancer