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Interleukin-4 receptor targeted immunotherapy of human bladder cancer in animal models
  1. Bharat H Joshi1,
  2. Akiko Suzuki2,
  3. Pamela Leland2,
  4. Samir Lababidi3,
  5. Frederick Varrichio4,
  6. Robert Kreitman5 and
  7. Raj K Puri1
  1. Aff1 grid.417587.80000000122433366Division of Cellular and Gene Therapies, Center for Biologics Evaluation and ResearchFDA Bethesda USA
  2. Aff2 grid.417587.80000000122433366CBERFDA USA
  3. Aff3 grid.417587.80000000122433366CBERFDA Silver Spring USA
  4. Aff4 grid.417587.80000 0001 2243 3366CBERFDA Wakefield USA
  5. Aff5 grid.94365.3d0000000122975165NCINIH USA

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Meeting abstracts

Previously, we have demonstrated that Interleukin-4 (IL-4) receptor alpha (IL-4Rα) is overexpressed in bladder cancer biopsy specimens and its expression level correlates with the grade and stage of disease. Based on these observations, it is proposed that IL-4Rα is a prognostic biomarker for bladder cancer. To target IL-4Rα, we have developed a recombinant chimeric fusion immunotoxin, which consists of circularly permuted IL-4 and truncated Pseudomonas exotoxin (IL-4-PE) [1]. Here we demonstrate that IL-4-PE is highly cytotoxic to eight bladder cancer cell lines in vitro. The cytotoxicity by IL-4-PE was mediated in a concentration dependent manner and this cytotoxicity was receptor specific as excess IL-4 inhibited cytotoxicity mediated by IL-4-PE. IL-4-PE immunotoxin also killed bladder cancer colonies in a concentration dependent manner in a clonogenic assay. We developed three subcutaneous tumor models in athymic nude mice using three different bladder cancer cell lines (UM-UC-3, SW780 and 5637), which are sensitive to IL-4-PE at a variable degree. These mice were treated with 50 μg/kg, 100 μg/kg of IL-4-PE immunotoxin or vehicle-control intratumorally and monitored for tumor growth and survival. IL-4-PE effectively caused regression of tumors by 70% in all three tumor models compared to vehicle control mice. Responding animals showed complete regression of tumors in 58% of mice at the highest dose in UM-UC-3 tumor model and 54% in SW780 tumor model. Overall, all responding animals showed >8 week longer survival compared to control mice. IL-4-PE immunotoxin at both doses did not show any visible toxicity when administrated intratumorally. Similar safety profile has been observed in the clinic when IL-4-PE was administered intratumorally in glioma trial [2]. Taken together our results demonstrate that IL-4Rα in bladder cancer is a prognostic biomarker and in addition it provides an excellent target for immunotherapy. Additional studies are ongoing to target IL-4Rα with other immunotherapeutic approaches such as cancer vaccines and adoptive cell transfer immunotherapy.


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