IL-13 cytotoxin has potent antitumor activity and synergizes with paclitaxel in a mouse model of oral squamous cell carcinoma

Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
International Journal of Cancer (Impact Factor: 5.09). 03/2009; 124(6):1440-8. DOI: 10.1002/ijc.24067
Source: PubMed


Interleukin-13 receptor-targeted cytotoxin (IL13-PE38) is highly cytotoxic to certain types of human cancers expressing abundant levels of IL-13Ralpha2 chain. Although IL13-PE38 is being tested in a Phase III clinical trial in brain tumors, the activity of IL13-PE38 alone or when combined with taxane, a chemotherapeutic drug for oral squamous cell carcinoma (OSCC), has not been investigated. Here, we show that approximately 40% of OSCCs (n = 50) in a tissue array are strongly positive for IL-13Ralpha2, whereas normal oral mucosa (n = 10) expresses very low or undetectable levels evaluated by immunohistochemistry. IL13-PE38 was highly cytotoxic to OSCC cell lines, but not cytotoxic to normal oral fibroblasts. IL13-PE38 mediated a synergistic antitumor effect with paclitaxel in OSC-19 in vitro and in vivo in the orthotopic OSCC tongue tumor model. Real-time tumor growth was monitored by optical imaging using a Xenogen-IVIS imaging system. Treated animals showed significant (p < 0.05) improvement in survival, which correlated with in vivo imaging of tumor response without evidence of visible toxicity. Gene transfer of IL-13Ralpha2 in oral cancer cells increased sensitivity of OSCC cell line to IL13-PE38 in vitro. Retrovirus-mediated gene-transfer of IL-13Ralpha2 in HSC-3 into tongue tumors in vivo dramatically enhanced the antitumor activity of IL13-PE38, providing complete elimination of established tumors and prolonging survival of these animals. These results indicate that IL13-PE38 in combination with paclitaxel acting via different mechanisms may be a potential treatment option for IL-13Ralpha2 expressing OSCC or for the treatment of non-IL-13Ralpha2 expressing OSCC combined with gene transfer of IL-13Ralpha2.

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Available from: Mitomu Kioi, Nov 26, 2014
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    • "Other treatment delivery options for IL-13-PE could improve the effectiveness of this immunotoxin in the Tgfbr1/Pten 2cKO mice such as direct injection into the head and neck tumors or a surgically implanted continuous infusion pump [22]. IL-13-PE has also been shown to work synergistically with paclitaxel in an immunodeficient animal model of HNSCC [29] with gemcitabine for pancreatic cancer [30] and a DNA vaccine of IL-13Rα2 in melanoma, breast, and sarcoma tumor models [20]. It is therefore possible that any of these combinations would be useful for testing the Tgfbr1/Pten 2cKO mouse model of spontaneous cancer. "
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    ABSTRACT: The sixth leading class of cancer worldwide is head and neck cancer, which typically arise within the squamous epithelium of the oral mucosa. Human head and neck squamous cell carcinoma (HNSCC) is known to be difficult to treat and has only a 50% five-year survival rate. With HNSCC, novel therapeutics are needed along with a means of rapidly screening anti-cancer agents in vivo, such as mouse models. In order to develop new animal models of cancer to test safety and efficacy of novel therapeutic agents for human HNSCC, tumors resembling clinical cases of human HNSCC were induced in the head and neck epithelium of a genetically engineered mouse model. This mouse model was generated by conditional deletion of two tumor suppressors, Transforming Growth Factor-β Receptor 1 (TGFβRI) and Phosphatase and Tensin homolog (PTEN), in the oral epithelium. We discovered that the tumors derived from these Tgfbr1/Pten double conditional knockout (2cKO) mice over-expressed IL-13Rα2, a high affinity receptor for IL-13 that can function as a tumor antigen. To demonstrate a proof-of-concept that targeted therapy against IL-13Rα2 expression would have any antitumor efficacy in this spontaneous tumor model, these mice were treated systemically with IL-13-PE, a recombinant immunotoxin consisting of IL-13 fused to the Pseudomonas exotoxin A. Tgfbr1/Pten 2cKO mice when treated with IL-13-PE displayed significantly increased survival when compared to the untreated control mice. The untreated mice exhibited weight loss, particularly with the rapid onset of tongue tumors, but the treated mice gained weight while on IL-13-PE therapy and showed no clinical signs of toxicity due to the immunotoxin. Expression of IL-13Rα2 in tumors was significantly decreased with IL-13-PE treatment as compared to the controls and the number of myeloid-derived suppressor cells (MDSC) was also significantly reduced in the spleens of the IL-13-PE treated mice. Our study demonstrates that the Tgfbr1/Pten 2cKO mouse model of human HNSCC is a useful model for assessing antitumor activity of new cancer therapeutic agents, and that IL-13-PE has therapeutic potential to treat human head and neck cancer.
    Full-text · Article · Feb 2013 · Journal of Translational Medicine
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    • "In a study by Puri and coworkers, the type I receptors were found to be overexpressed on a variety of cancers including renal cell carcinoma, glioma, and ovarian adenocarcinomas.36,40,50,51,80 In another study, Puri’s group investigated type I IL-13R expression in 25 brain tumor explants, as well as normal human astrocyte cultures and normal brain tissue. "
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    ABSTRACT: Overexpressed receptors, characteristic of many cancers, have been targeted by various researchers to achieve a more specific treatment for cancer. A common approach is to use the natural ligand for the overexpressed receptor as a cancer-targeting agent which can deliver a chemically or genetically conjugated toxic molecule. However, it has been found that the therapeutic efficacy of such ligand-drug molecular conjugates can be limited, since they naturally follow the intracellular trafficking pathways of the endogenous ligands. Therefore, a thorough understanding of the intracellular trafficking properties of these ligands can lead to novel design criteria for engineering ligands to be more effective drug carriers. This review presents a few commonly used ligand/receptor systems where intracellular trafficking considerations can potentially improve the therapeutic efficacy of the ligand-drug molecular conjugates.
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    • "IL-13 receptor complex exists at least in two diVerent types, IL-13R1 and IL-13R2, in which IL-13R2 chain is a major binding component of the IL-13R complex and has a high aYnity with IL-13. IL-132 is overexpressed in many diVerent types of cancer cells including gliomas, human pediatric brain tumors, AIDS- Kaposi's sarcoma, Ovarian cancer, oral squamous cell carcinoma, and other human head and neck cancer, but not expressed at a very low level in corresponding normal human cells (Joshi et al. 2000; Husain and Puri 2000; Kawakami et al. 2003 Kawakami et al. , 2004a Kioi et al. 2006 Kioi et al. , 2009). Some other researches demonstrated that the combination approach of injecting IL-13R2 plasmid in established tumors followed by IL-13 cytotoxin administration showed profound antitumor activity against human breast tumors in xenografted immunodeWcient mice (Kawakami et al. 2004a, b ). "
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    ABSTRACT: Liver cancer is the third leading cause of cancer-related deaths globally. The number of liver cancers diagnosed in the world is increasing at an alarming rate. It is of great significance to find the new targets of the tumor cells and specific medicine. This research investigated the expression of interleukin-13 receptor alpha2 (IL-13Ralpha2) in different liver cancer cell lines and liver cancer tissues, and assessed the cytotoxin DT389-hIL13-13E13K (IL-13 and diphtheria toxin fusion protein) targeted killing effect on liver cancer cells. Based on study above, we further analyzed the function of IL-13Ralpha2 on the targeted liver cancer therapy. The results will provide a novel strategy and an alternative way for liver cancer therapy. The expression of IL-13Ralpha2 in different liver cancer cell lines and tissues were analyzed by RT-PCR and immunohistochemistry. Cytotoxicity assay of DT389-hIL13-13E13K was performed in eight different concentrations in liver cancer cell lines in vitro. At the same time, siRNA-mediated knockdown was introduced to assess the role of IL-13Ralpha2 in liver cancer therapy. Two out of four tested liver cancer cell lines and 27 out of 33 (81.82%) liver tissues expressed the IL-13Ralpha2. The fusion protein DT(389)-hIL13-13E13K showed a moderate cytotoxicity to the cancer cell line BEL-7402 in vitro, which 50% inhibition (IC(50)) concentration occurred at 1.4 x 10(-5 )M. Besides, the sensitivity to fusion protein DT(389)-hIL13-13E13K was decreased in siRNA-transfected liver cells compared with control ones. These results suggest that IL-13Ralpha2 chain is a specific target for IL-13-directed fusion protein. We reported the expression of IL-13Ralpha2 in liver cancer cell lines and tissues as well as investigated the cytotoxin (DT389-hIL13-13E13K) targeted killing efficiency of liver cancer cells and potential role of IL-13Ralpha2 in the cancer treatment.
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