Convection-Enhanced Delivery of Cintredekin Besudotox (Interleukin-13-Pe38qqr) Followed by Radiation Therapy With and Without Temozolomide in Newly Diagnosed Malignant Gliomas

Vogelbaum, Michael A.; Sampson, John H.; Kunwar, Sandeep; Chang, Susan M.; Shaffrey, Mark E.; Asher, Anthony L.; Lang, Frederick F.; Croteau, David; Parker, Kristen; Grahn, Amy; Sherman, Jeffrey W.; Husain, Syed R.; Puri, Raj K.

doi:10.1227/01.neu.0000303199.77370.9e

Cited by 122 publications

(59 citation statements)

References 25 publications

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“…On the other hand, a single intratumoral administration of the protein formulations led to lower antitumor efficacy; that is, Cintredekin Besudotox doubled the median survival and all of the animals succumbed to tumor burden, and the second-generation mhIL-13-PE protein formulation elicited ∼40% long-term survival. These results suggest that the short half-life of the protein formulations (16,17) can be overcome by Ads, which allow sustained local expression.…”

Section: Discussionmentioning

confidence: 88%

“…Because IL13Rα2 is virtually absent from normal brain cells (14), human IL-13 was fused to a truncated Pseudomonas exotoxin (hIL-13-PE; Cintredekin Besudotox) to target IL13Rα2-expressing GBM cells (15). Due to the short half-life of the hIL-13-PE protein formulation (16,17), multiple injections or continued delivery was necessary to achieve therapeutic levels (1,16,18). This approach was tested preclinically and in phase I-III clinical trials (16)(17)(18).…”

mentioning

confidence: 99%

“…Due to the short half-life of the hIL-13-PE protein formulation (16,17), multiple injections or continued delivery was necessary to achieve therapeutic levels (1,16,18). This approach was tested preclinically and in phase I-III clinical trials (16)(17)(18). However, in spite of high expectations, the phase III trial failed to achieve clinical endpoints (http://www.fiercebiotech.…”

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confidence: 99%

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Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

Candolfi

Xiong

Yagiz

et al. 2010

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

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Restricting the cytotoxicity of anticancer agents by targeting receptors exclusively expressed on tumor cells is critical when treating infiltrative brain tumors such as glioblastoma multiforme (GBM). GBMs express an IL-13 receptor (IL13Rα2) that differs from the physiological IL4R/IL13R receptor. We developed a regulatable adenoviral vector (Ad.mhIL-4.TRE.mhIL-13-PE) encoding a mutated human IL-13 fused to Pseudomonas exotoxin (mhIL-13-PE) that specifically binds to IL13Rα2 to provide sustained expression, effective anti-GBM cytotoxicity, and minimal neurotoxicity. The therapeutic Ad also encodes mutated human IL-4 that binds to the physiological IL4R/IL13R without interacting with IL13Rα2, thus inhibiting potential binding of mhIL-13-PE to normal brain cells. Using intracranial GBM xenografts and syngeneic mouse models, we tested the Ad.mhIL-4.TRE.mhIL-13-PE and two protein formulations, hIL-13-PE used in clinical trials (Cintredekin Besudotox) and a second-generation mhIL-13-PE. Cintredekin Besudotox doubled median survival without eliciting long-term survival and caused severe neurotoxicity; mhIL-13-PE led to ∼40% long-term survival, eliciting severe neurological toxicity at the high dose tested. In contrast, Ad-mediated delivery of mhIL-13-PE led to tumor regression and long-term survival in over 70% of the animals, without causing apparent neurotoxicity. Although Cintredekin Besudotox was originally developed to target GBM, when tested in a phase III trial it failed to achieve clinical endpoints and revealed neurotoxicity. Limitations of Cintredekin Besudotox include its short half-life, which demanded frequent or continued administration, and binding to IL4R/IL13R, present in normal brain cells. These shortcomings were overcome by our therapeutic Ad, thus representing a significant advance in the development of targeted therapeutics for GBM.

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Section: Discussionmentioning

confidence: 88%

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confidence: 99%

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confidence: 99%

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Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

Candolfi

Xiong

Yagiz

et al. 2010

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

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“…Recent clinical trials testing PE38-based anti-cancer agents for the treatment of mesothelioma and glioma revealed that 73 and 88% of the patients respectively developed neutralising IgG antibodies, with one study showing the majority of the antibodies were directed to the toxin fragment of the molecule Vogelbaum et al, 2007). To address this issue, Onda and Pastan used serum samples from patients receiving a BL22, a PE38-containing anti-leukemia agent, to map out regions of the molecule that elicited the strongest antibody response .…”

Section: Discussionmentioning

confidence: 99%

Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity

Stish

Chen

et al. 2009

Br J Cancer

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BACKGROUND: Potency, immunogenicity, and toxicity are three problems that limit the use of targeted toxins in solid tumour therapy. METHODS: To address potency, we used genetic engineering to develop a novel bispecific ligand-directed toxin (BLT) called EGF4KDEL, a novel recombinant anti-mesothelioma agent created by linking human epidermal growth factor (EGF) and interleukin-4 (IL-4) to truncated pseudomonas exotoxin (PE38) on the same single-chain molecule. Immunogenicity was reduced by mutating seven immunodominant B-cell epitopes on the PE38 molecule to create a new agent, EGF4KDEL 7Mut. RESULTS: In vitro, bispecific EGF4KDEL showed superior anti-mesothelioma activity compared with its monospecific counterparts. Toxicity in mice was diminished by having both ligands on the same molecule, allowing administration of a 10-fold greater dose of BLT than a mixture of monomeric IL4KDEL and EGFKDEL. EGF4KDEL 7Mut, retained all of its functional activity and induced about 87% fewer anti-toxin antibodies than mice given the parental, non-mutated form. In vivo, intraperitoneal (IP) injection of the BLT showed significant (Po0.01) and impressive effects against two aggressive, malignant IP mesothelioma models when treatment was begun 14-16 days post tumour innoculation. CONCLUSION: These data show that EGF4KDEL 7Mut is a promising new anti-mesothelioma agent that was developed to specifically address the obstacles facing clinical utility of targeted toxins.

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“…47,48 A phase I study of CED of IL13-PE38QQR followed by radiation therapy with and without temozolomide in newly diagnosed malignant glioma revealed a well-tolerated therapy in these patients. 49 …”

Section: Il-4 and Il-13 Targeted Toxinsmentioning

confidence: 99%

Novel Drug Delivery Strategies in Neuro-Oncology

Bidros

Vogelbaum

2009

Neurotherapeutics

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Summary: Treatment of malignant gliomas represents one of the most formidable challenges in oncology. Despite treatment with surgery, radiation therapy, and chemotherapy, the prognosis remains poor, particularly for glioblastoma, which has a median survival of 12 to 15 months. An important impediment to finding effective treatments for malignant gliomas is the presence of the blood brain barrier, which serves to prevent delivery of potentially active therapeutic compounds. Multiple efforts are focused on developing strategies to effectively deliver active drugs to brain tumor cells. Blood brain barrier disruption and convectionenhanced delivery have emerged as leading investigational delivery techniques for the treatment of malignant brain tumors. Clinical trials using these methods have been completed, with mixed results, and several more are being initiated. In this review, we describe the clinically available methods used to circumvent the blood brain barrier and summarize the results to date of ongoing and completed clinical trials. Key Words: Convection-enhanced delivery, blood brain barrier disruption, brain neoplasm, drug delivery system.

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Convection-Enhanced Delivery of Cintredekin Besudotox (Interleukin-13-Pe38qqr) Followed by Radiation Therapy With and Without Temozolomide in Newly Diagnosed Malignant Gliomas

Abstract: CB (0.5 microg/mL) administered via convection-enhanced delivery before standard radiochemotherapy seems to be well tolerated in adults with newly diagnosed malignant gliomas. Further clinical study assessment is warranted.

Cited by 122 publications

References 25 publications

Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity

Novel Drug Delivery Strategies in Neuro-Oncology

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