EAU 2018: Low Dose Gemcitabine Increases the Cytotoxicity of Human γδT Cell in In Vitro and in an Orthotopic Xenograft Model in Bladder Cancer

Copenhagen, Denmark (UroToday.com) There has long been an effort to identify an effective salvage therapy for NMIBC patients who fail intravesical BCG. Unfortunately, at this time, radical cystectomy remains the best option for these patients. Many agents have been tested and failed to demonstrate significant benefit. However, many newer agents, including immunotherapy agents, are currently in clinical trial. The advantages of an effective BCG salvage are obvious – avoiding cystectomy is an important goal for many patients and physicians, due to the significant impact on patients QOL.

In this study, the authors focus on γδT-cell immunotherapy. γδT-cells, a subset of T-cells, exert potent cytotoxicity towards various cancer cells and can recognize isopentenyl pyrophosphate (IPP) through the TCRγδ receptor, and zoredronic acid (ZOL) pretreatment is widely used to induce IPP accumulation in cancer cells. They note that systemic attempts have been generally unsuccessful. As such, they assessed the combined use of anticancer agents along with ZOL and assessed an intravesical approach for NMIBC. 

The study was a basic science model, combining an in-vitro approach followed by an orthotopic mouse model. They first completed cytotoxicity assays on established cancer cell lines. Then, the efficacy of ex vivo-expanded γδT cell immunotherapy was examined in an orthotopic xenograft model using In Vivo Imaging System (IVIS).

They first expanded γδT cells from the peripheral blood of a healthy volunteer. Ex vivo-expanded γδT cells showed potent cytotoxicity against UBC cells (T24, TCCSUP, and UMUC3) in in vitro assays. Combination treatment with standard anticancer agents showed that low dose gemcitabine pretreatment significantly enhanced the cytotoxicity of γδT cells by upregulating the expression of MICA and MICB (MICA/B), which are tumor-associated antigens recognized by γδT cells. These effects were abrogated by small interfering RNA-mediated knockdown of MICA/B in UBC cells. 

In their orthotopic mouse model, IVIS analysis revealed the potent cytotoxicity of weekly intravesical administration of γδT cells. They had 2 mice treated with placebo, 2 treated with γδT cells – mice treated with placebo had progression of disease over 4 weeks, while the 2 mice treated with γδT cells had excellent response. They presented similar results on the poster of the repeat assessments. Weekly gemcitabine pretreatment enhanced the cytotoxicity of γδT cells in in vivo, similar to in-vitro studies. 

Based on this, the authors conclude that low dose gemcitabine pretreatment significantly enhanced the cytotoxicity of γδT cells by up regulating the expression MICA/B in in vitro, and that intravesical γδT cell immunotherapy exerted potent cytotoxicity against UBC. Therefore, intravesical γδT cell immunotherapy in combination with low dose gemcitabine may be a promising strategy in BCG failure NMIBC. 


Presented by:  T. Shimizu, MD

Co-Authors: Miyashita M., Tomogane M., Ukimura O., Ashihara E

Written by: Thenappan Chandrasekar, MD Clinical Fellow, University of Toronto, twitter: @tchandra_uromd at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark