PD33-10 RADIATION THERAPY IMPROVES IMMUNOGENICITY OF HUMAN RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2015PD33-10 RADIATION THERAPY IMPROVES IMMUNOGENICITY OF HUMAN RENAL CELL CARCINOMA Jason Muhitch, Mohammad Habiby Kermany, Lilia Heit, Alexander Wald, Mary Hensen, Scott Abrams, Timothy Winslow, Anurag Singh, and Thomas Schwaab Jason MuhitchJason Muhitch More articles by this author , Mohammad Habiby KermanyMohammad Habiby Kermany More articles by this author , Lilia HeitLilia Heit More articles by this author , Alexander WaldAlexander Wald More articles by this author , Mary HensenMary Hensen More articles by this author , Scott AbramsScott Abrams More articles by this author , Timothy WinslowTimothy Winslow More articles by this author , Anurag SinghAnurag Singh More articles by this author , and Thomas SchwaabThomas Schwaab More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2108AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Metastatic Renal Cell Carcinoma (RCC) is a lethal disease and the only curative approach is highly toxic immunotherapy via high-dose IL-2 treatment. For anti-tumor immunotherapy to be effective, CD8 T cells must detect tumor-associated antigens (TAA) presented on tumor cells to initiate contact-dependent cell lysis. Radiation has been shown to induce TAA expression in a variety of malignancies and is generally well-tolerated compared to high-dose IL-2. The recent advent of Stereotactic Body Radiation Therapy (SBRT) allows delivery of high-dose radiation to a well-defined target area with limited damage to normal tissue and is being explored in the treatment of RCC. We therefore sought to determine if TAA expression was increased following SBRT treatment of metastatic RCC tumors in a first of its kind Phase I clinical trial where patients are treated with neo-adjuvant SBRT followed by surgical resection. These studies were complemented with in vitro studies that examined TAA expression in radiated human RCC cell lines. METHODS RCC human cells lines (A498, A704, 769-P, 786-0, ACHN, and Caki-1) were treated ± radiation (16 Gy). 0 - 96 h later, TAA and costimulatory molecule expression was evaluated by flow cytometry. ELISPOT IFN-ã release assays were performed with NY-ESO-1 specific HLA-A2-restricted CD8+ T cell clones. Stage IV Renal Cell Carcinoma patients were treated ± SBRT and ∼28 days later tumors were resected (clinical trial NCT01892930). Single cell suspensions of resected tumors were evaluated for TAA and costimulatory molecules by flow cytometry. RESULTS Initial studies determined that high-dose radiation treatment improved TAA expression (NY-ESO-1, MUC-1, CA9) and costimulatory molecule expression (CD80, ICAM-1) in six commercially available RCC human cells lines. NY-ESO-1 specific CD8 T cells secreted more IFN-ã in response to radiated RCC cell lines (149.7 ± 57.1, mean ± SD per 50,000 cells) compared to control (19.7 ± 9.7, P < 0.05). Surprisingly, we also found that RCC tumors from patients treated with SBRT and later resected also showed improved expression of the TAA MUC-1, CA-9, and 5T4 (P < 0.05) and NY-ESO-1 (P < 0.07) compared to age-matched RCC patient tumors. Expression of the costimulatory molecules ICAM-1 and CD80 were also increased in SBRT-treated patient tumors compared to resected tumors from age-matched controls. CONCLUSIONS By increasing TAA and costimulatory molecule expression, SBRT treatment of RCC may unlock anti-tumor immune responses that can be further amplified with vaccination protocols and immune checkpoint blockade strategies. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e713 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jason Muhitch More articles by this author Mohammad Habiby Kermany More articles by this author Lilia Heit More articles by this author Alexander Wald More articles by this author Mary Hensen More articles by this author Scott Abrams More articles by this author Timothy Winslow More articles by this author Anurag Singh More articles by this author Thomas Schwaab More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...