Interleukin-13 Displaying Retargeted Oncolytic Measles Virus Strains Have Significant Activity Against Gliomas With Improved Specificity

Allen, Cory; Paraskevakou, Georgia; Iankov, Ianko; Giannini, Caterina; Schroeder, Mark A.; Sarkaria, Jann N.; Puri, Raj K.; Russell, Stephen J.; Galanis, Evanthia

doi:10.1038/mt.2008.152

Cited by 75 publications

(69 citation statements)

References 39 publications

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“…Considering the limitations of human GBM xenografts derived from cell lines, namely the loss of certain features present in human GBMs due to prolonged in vitro passage, we tested the efficacy of the therapeutic Ad in an intracranial human primary GBM12 tumor, which is a transplantable human tumor that retains the biological and histological properties of the original human GBM specimen (25,26), including epidermal growth factor receptor amplification (26), TP53 mutation (26), and expression of IL13Rα2 (25). We implanted GBM12 cells from short-term cultures in the brain of Rag1 −/− mice and treated them 5 d later with the therapeutic and control vectors or, as controls, saline or an empty Ad (Ad.0).…”

Section: Efficacy and Neurotoxicity Of Therapeutic Ads In Intracraniamentioning

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: Efficacy and Neurotoxicity Of Therapeutic Ads In Intracraniamentioning

confidence: 99%

“…Human GBM xenografts. Intracranial U251 xenografts in athymic nude BALB/c mice and human primary GBM12 (kindly donated by Evanthia Galanis, Department of Oncology, Mayo Clinic and Foundation, Rochester, MN) xenografts in Rag1 −/− mice were established as previously described (25,26,35) (SI Appendix, SI Materials and Methods).…”

Section: Si Appendixmentioning

confidence: 99%

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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“…7 Measles virus (MV) vectors based on the vaccinelineage MV-Edmonston have proven to be a platform with broad utility, having been developed for the treatment of several types of cancer in preclinical settings. [8][9][10][11][12][13][14][15][16] Since 2005, clinical trials including Phase I studies for treatment of ovarian cancer, myeloma and recurrent glioma are going on. [17][18][19] Currently, improved specificity and efficacy are the main aims in the process of rational MV vector design.…”

Section: Introductionmentioning

confidence: 99%

Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus

et al. 2011

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First-line treatment of recurrent and/or refractory head and neck squamous cell carcinoma (HNSCC) is based on platinum, 5-fluorouracil (5-FU) and the monoclonal antiEGFR antibody cetuximab. However, in most cases this chemoimmunotherapy does not cure the disease, and more than 50% of HNSCC patients are dying because of local recurrence of the tumors. In the majority of cases, HNSCC overexpress the epidermal growth factor receptor (EGFR), and its presence is associated with a poor outcome. In this study, we engineered an EGFR-targeted oncolytic measles virus (MV), armed with the bifunctional enzyme cytosine deaminase/ uracil phosphoribosyltransferase (CD/UPRT). CD/UPRT converts 5-fluorocytosine (5-FC) into the chemotherapeutic 5-FU, a mainstay of HNSCC chemotherapy. This virus efficiently replicates in and lyses primary HNSCC cells in vitro. Arming with CD/UPRT mediates efficient prodrug activation with high bystander killing of non-infected tumor cells. In mice bearing primary HNSCC xenografts, intratumoral administration of MV-antiEGFR resulted in statistically significant tumor growth delay and prolongation of survival. Importantly, combination with 5-FC is superior to virus-only treatment leading to significant tumor growth inhibition. Thus, chemovirotherapy with EGFR-targeted and CD/UPRT-armed MV is highly efficacious in preclinical settings with direct translational implications for a planned Phase I clinical trial of MV for locoregional treatment of HNSCC.

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“…Taking into account broad variability of glioma cellular surface markers, exploring the differential expression of proteins on the surface of cancer cells is the key to targeting glioma and therapeutic payloads. For example, previous studies utilized targeting to transferrin, IL13 and IL4 receptors [8]. The EGFR are frequently overexpressed in head and neck, metastatic colorectal, lung cancers and GBM tumors.…”

Section: -Written By Joonseok Leementioning

confidence: 99%