585 IL-15 ANALOGUE (ALT-803) TARGETING T REGULATORY CELLS CAUSES TUMOR BURDEN REDUCTION IN AN ORTHOTOPIC NON-MUSCLE INVASIVE BLADDER CANCER MODEL (2013)

You have accessJournal of UrologyBladder Cancer: Basic Research (I)1 Apr 2013585 IL-15 ANALOGUE (ALT-803) TARGETING T REGULATORY CELLS CAUSES TUMOR BURDEN REDUCTION IN AN ORTHOTOPIC NON-MUSCLE INVASIVE BLADDER CANCER MODEL Evan Gomes, Makito Miyake, Ge Zhang, Steven Goodison, Jack Egan, Peter Rhode, Hing Wong, and Charles Rosser Evan GomesEvan Gomes Orlando, FL More articles by this author , Makito MiyakeMakito Miyake Orlando, FL More articles by this author , Ge ZhangGe Zhang Orlando, FL More articles by this author , Steven GoodisonSteven Goodison Orlando, FL More articles by this author , Jack EganJack Egan Miramar, FL More articles by this author , Peter RhodePeter Rhode Miramar, FL More articles by this author , Hing WongHing Wong Miramar, FL More articles by this author , and Charles RosserCharles Rosser Orlando, FL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1981AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES A recent NCI review listed IL-15 as the most promising product candidate among twelve immunotherapy drugs that could potentially cure cancer. Preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15R Á-Fc fusion) have shown promising results for obtaining prolonged drug half-life and stimulating CD8+ T cells and NK cells. Based on these encouraging results, we hypothesized that the administration of ALT-803 will generate an immunologic response which will reduce tumor burden in a rodent carcinogen induced orthotopic non muscle invasive bladder cancer model. METHODS We tested intravesical ALT-803 alone and ALT-803 in combination with BCG in a rodent carcinogen induced orthotopic non-muscle invasive bladder cancer model. Rats were anesthetized with isoflurane then a 22-gauge Teflon angiocatheter (transurethral catheter) was placed in the bladder and urine completely drained from the bladder. Next, the saline (negative control), ALT-803 (experimental agent) or BCG (positive control) therapy was delivered by transurethral instillation through the transurethral catheter and allowed to dwell in the bladder for 1 hr by occlusion of the urethra with a purse string suture. The intravesical therapy was administered weekly for a total of six weeks to mimic intravesical BCG therapy in humans. RESULTS Herein we demonstrate that intravesical ALT-803 was safe and well tolerated alone or in combination with intravesical Bacillus Calmette-Gu¿rin (BCG). Furthermore, ALT-803 alone reduced tumor burden by 23% compared to control whereas BCG alone reduced tumor burden by 11% compared to control. The combination of ALT-803 and BCG reduced tumor burden by 30% compared to control. Tumoral responses of the combinational treatment were associated with 76% and 80% reduction (compared to control) in angiogenesis and proliferation, respectively, whereas combinational therapy was associated with a 7.7-fold increase in apoptotic index compared to control. Immune monitoring suggested that the antitumor response was linked to the activation of CD8+ cells and NK cells as well as the secretion of the immune and inflammatory regulatory factors IL1&cjs3742;Á, IL1&cjs3742;Â, IL2, and RANTES in the serum and IL1&cjs3742;Á, IL1&cjs3742;Â, TNF&cjs3742;Á, IL4, IL13 and RANTES in the urine. CONCLUSIONS The enhanced therapeutic index provided by the addition of ALT-803 to BCG therefore provides a powerful justification for the development of this agent for future clinical trials in subjects with non-muscle invasive bladder cancer. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189 Issue 4S April 2013 Page: e239 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.Metrics Author Information Evan Gomes Orlando, FL More articles by this author Makito Miyake Orlando, FL More articles by this author Ge Zhang Orlando, FL More articles by this author Steven Goodison Orlando, FL More articles by this author Jack Egan Miramar, FL More articles by this author Peter Rhode Miramar, FL More articles by this author Hing Wong Miramar, FL More articles by this author Charles Rosser Orlando, FL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...