Serdar Celik1, Aylin Erol2, Ozde Gokbayrak2, Hilmi Sari3, Batuhan Yilmaz3, Mehmet Ugur Mungan4, Kutsal Yorukoglu5, Guven Aslan6, Ilhan Celebi3, Zekiye Altun7, Tugba Yavuzsen8, Safiye Aktas9
1Health Sciences University, Izmir Bozyaka Training and Research Hospital, Department of Urology, Izmir, Turkey.
2Dokuz Eylul University, Institute of Oncology, Department of Basic Oncology, Izmir, Turkey.
3Dokuz Eylul University, School of Medicine, Department of Urology, Izmir, Turkey.
4Dokuz Eylul University, School of Medicine, Department of Pathology, Izmir, Turkey.
5Dokuz Eylul University, School of Medicine, Department of Internal Medicine, Division of Medical Oncology, Izmir, Turkey.
Summary
Purpose: To study the ex-vivo efficacy of immunotherapeutic agents as an oncogram in primary bladder cancer cell cultures obtained from patients with intermediate-risk and high-risk non-muscle invasive bladder cancer (NMIBC) and its possible relationships with clinicopathologic features were evaluated.
Methods: Primary bladder cancer cell cultures were produced from each tissue sample. Each culture was divided into 5 drug administration groups. In Group-1, mononuclear cells (MNCs) were isolated from blood samples and non-treated primary cells only were used. Besides MNCs, mitomycin-C (MMC) for Group-2, Bacillus Calmette Guérin (BCG) for Group-3, nivolumab for Group-4 and ipilimumab for Group-5 were applied. Viability tests were performed using WST-1. Expressions of programmed death-1, its ligands (PD-1, PD-L1 and PD-L2, respectively) and cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) were investigated immunohistochemically (IHC).
Results: Tumoral PD-1 positivity was found to be significantly associated with worse pathologic outcomes. All agents caused lower viability rates. Good response rates of PD-L1 positive cases were significantly higher compared to PD-L1 negative cases after the MMC (66% vs 0%, p=0.045) and nivolumab (66% vs 0%, p=0.045) treatments. Also, good response rate after MMC was found higher only in high-risk cases with peritumoral PD-1 positive than negatives (87.5% vs 20%, p=0.032).
Conclusions: Drug responses, namely oncogram results of MMC, BCG, nivolumab and ipilimumab were found significantly higher than in controls. Although, there were some differences based on IHC between the patients, nivolumab response rate was better especially in PD-L1 positive patients.
Key words: Bacillus Calmette Guerin (BCG), ipilimumab, nivolumab, non-muscle invasive bladder cancer (NMIBC), Oncogram.
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