304 DC-AD-GMCAIX BASED VACCINE THERAPY IS SAFE AND EFFECTIVE IN IMMUNOCOMPETENT MURINE KIDNEY CANCER TUMOR MODELS (2012)

You have accessJournal of UrologyKidney Cancer: Basic Research II1 Apr 2012304 DC-AD-GMCAIX BASED VACCINE THERAPY IS SAFE AND EFFECTIVE IN IMMUNOCOMPETENT MURINE KIDNEY CANCER TUMOR MODELS Frédéric D. Birkhäuser, Richard C. Koya, Caleb Neufeld, Xuyang Lu, Ewa D. Micewicz, Thinle Chodon, Mohammad Atefi, Nils Kroeger, Edward N. Rampersaud, Gadisetti V.R. Chandramouli, Gang Li, Jonathan W. Said, Antoni Ribas, William H. McBride, Fairooz F. Kabbinavar, Allan J. Pantuck, Arie S. Belldegrun§, and Joseph Riss§ Frédéric D. BirkhäuserFrédéric D. Birkhäuser Los Angeles, CA More articles by this author , Richard C. KoyaRichard C. Koya Los Angeles, CA More articles by this author , Caleb NeufeldCaleb Neufeld Los Angeles, CA More articles by this author , Xuyang LuXuyang Lu Los Angeles, CA More articles by this author , Ewa D. MicewiczEwa D. Micewicz Los Angeles, CA More articles by this author , Thinle ChodonThinle Chodon Los Angeles, CA More articles by this author , Mohammad AtefiMohammad Atefi Los Angeles, CA More articles by this author , Nils KroegerNils Kroeger Los Angeles, CA More articles by this author , Edward N. RampersaudEdward N. Rampersaud Los Angeles, CA More articles by this author , Gadisetti V.R. ChandramouliGadisetti V.R. Chandramouli Columbia, MD More articles by this author , Gang LiGang Li Los Angeles, CA More articles by this author , Jonathan W. SaidJonathan W. Said Los Angeles, CA More articles by this author , Antoni RibasAntoni Ribas Los Angeles, CA More articles by this author , William H. McBrideWilliam H. McBride Los Angeles, CA More articles by this author , Fairooz F. KabbinavarFairooz F. Kabbinavar Los Angeles, CA More articles by this author , Allan J. PantuckAllan J. Pantuck Los Angeles, CA More articles by this author , Arie S. Belldegrun§Arie S. Belldegrun§ Los Angeles, CA More articles by this author , and Joseph Riss§Joseph Riss§ Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.363AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES § co-corresponding; We previously reported the successful ex vivo generation and priming of CAIX-specific, MHC restricted cytotoxic T lymphocytes (CTLs) by adenoviral (Ad) transduction of the GM-CAIX fusion protein in dendritic cells (DC). Our current study tests, for the first time, the in vivo anti-tumor activity of DC-Ad-GMCAIX in preventing and intervening in the growth of renal cell carcinoma (RCC) in immunocompetent mice. METHODS Tumor growth inhibition and specificity were studied in BALB/c mice s.c. transplanted with either the syngeneic CAIX-expressing RCC cell line RENCA-CAIX (PRCAIX) or the non-CAIX-expressing parental RENCA line. In the preventative model, cohorts of mice were immunized s.c. twice 6 days apart with either DC-Ad-GMCAIX, DC-Ad-null, or no DC transplantation, followed by s.c. transplantation of PRCAIX or RENCA lines 12 days later. In the interventional model, tumors were first established and then immunotherapy was employed. Tumor volume and body weight were determined twice a week. At the end of each study, tumors were harvested, and partial necropsy, immunohistochemistry, and complete blood count were performed. RESULTS DC-Ad-GMCAIX expressed in vivo hCAIX protein that primed CTLs to specifically target hCAIX expressed by PRCAIX. In the preventative model, PRCAIX tumor growth was specifically and significantly inhibited for 15 days (all p<0.0001), reaching 79% median growth inhibition at termination (113 vs. 531 mm3). Half of the mice in the treatment cohort did not develop tumors. The results were confirmed by a repeated study (inhibition for 15 days; all p<0.0001; 7/8 mice without tumor at termination). In the interventional model, DC-Ad-GMCAIX-vaccinated mice demonstrated a specific and significant growth inhibition of PRCAIX-tumors for 8 days (all p<0.0018), with 60% median growth inhibition at termination (487 vs. 1,205 mm3). The therapeutic cohorts time to 15% weight loss were significantly longer (log-rank test p<0.0167). No vaccine-related weight loss or organ toxicity was observed. hCAIX staining was absent or minimally present in PRCAIX-tumors that evaded DC-Ad-GMCAIX therapy, compared to strong homogeneous staining in the negative control groups. CONCLUSIONS DC-Ad-GMCAIX therapy is capable of the in vivo generation of CAIX specific CTLs in immunocompetent mice, leading to significant RCC tumor growth inhibition without systemic toxicity. Additional studies are being conducted to analyze the immune response, and the differential global gene and miRNA expression of cells that evaded the therapy. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e123-e124 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Frédéric D. Birkhäuser Los Angeles, CA More articles by this author Richard C. Koya Los Angeles, CA More articles by this author Caleb Neufeld Los Angeles, CA More articles by this author Xuyang Lu Los Angeles, CA More articles by this author Ewa D. Micewicz Los Angeles, CA More articles by this author Thinle Chodon Los Angeles, CA More articles by this author Mohammad Atefi Los Angeles, CA More articles by this author Nils Kroeger Los Angeles, CA More articles by this author Edward N. Rampersaud Los Angeles, CA More articles by this author Gadisetti V.R. Chandramouli Columbia, MD More articles by this author Gang Li Los Angeles, CA More articles by this author Jonathan W. Said Los Angeles, CA More articles by this author Antoni Ribas Los Angeles, CA More articles by this author William H. McBride Los Angeles, CA More articles by this author Fairooz F. Kabbinavar Los Angeles, CA More articles by this author Allan J. Pantuck Los Angeles, CA More articles by this author Arie S. Belldegrun§ Los Angeles, CA More articles by this author Joseph Riss§ Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...