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. 2025 Jun;43(6):391.e1-391.e10.
doi: 10.1016/j.urolonc.2025.01.015. Epub 2025 Feb 15.

Impact of baseline PD-L1 status in BCG naive nonmuscle invasive bladder cancer on outcomes and changes after BCG exposure

Thomas Gerald  1 , Solomon L Woldu  2 , Daniel Halstuch  3 , Yaara Ber  3 , Karin Lifshitz  3 , Grayden Cook  2 , Franto Francis  4 , David Margel  3 , Liwei Jia  4 , Yair Lotan  2
Affiliations

Impact of baseline PD-L1 status in BCG naive nonmuscle invasive bladder cancer on outcomes and changes after BCG exposure

Thomas Gerald et al. Urol Oncol. 2025 Jun.

Abstract

Introduction: While BCG remains standard of care adjuvant treatment for high-risk nonmuscle invasive bladder cancer (NMIBC), predicting response to BCG therapy is difficult. PD-L1 expression in the tumor microenvironment is a biomarker which may impact the efficacy of immunotherapy. The purpose of this study is to determine the predicative ability of PD-L1 for BCG-unresponsiveness in BCG-naïve high-risk NMIBC.

Materials and methods: We performed a retrospective review of high-risk NMIBC patients treated with BCG in the United States (108) and Israel (124) from 2008 to 2014. PD-L1 status of BCG-naïve specimens determined with Dako 22c3 assay (CPS > 0) at initial transurethral resection was correlated with outcomes, primarily BCG-unresponsiveness. The impact of BCG exposure on PD-L1 expression was analyzed in patients who had sequential tumor sampling.

Results: Of 232 patients, 48 (21.6%) were BCG-unresponsive. PD-L1 expression was positive in 20 (9.2%) and in 5 (5.4%), 15 (14.3%), and 0 of Ta, T1, and CIS, respectively. In the US cohort, BCG-unresponsiveness occurred in 2 (14.3%) of PD-L1 positive and 36 (42.9%) of PD-L1 negative patients (P = 0.042). Tumors with baseline PD-L1 positivity were associated with a lower rate of BCG-unresponsiveness (OR 0.14; 95%CI 0.03-0.76). The predictive value of PD-L1 status in determining BCG-unresponsiveness was poor (AUC 0.57, 95%CI 0.46-0.69). Changes from PD-L1 negative to positive status after BCG exposure were observed, indicating a possible mechanism of resistance to BCG.

Conclusions: While PD-L1 status was an imperfect overall biomarker for BCG unresponsiveness, there was an association between initial PD-L1 expression and BCG response. Additionally, there was an upregulation of PD-L1 expression in BCG unresponsive specimens. These findings generate a hypothesis-generating discussion regarding the tumor immune-microenvironment and its response to BCG. Further investigation is necessary to better understand this interaction and its impact on tumor biomarker profiling and patient selection for combination therapy.

Keywords: BCG; Biomarker; Bladder cancer; PD-L1.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yair Lotan reports financial support was provided by National Cancer Institute of the National Institutes of Health. Yair Lotan reports financial support was provided by Delek Foundation Fund at the Communities Foundation of Texas. Yair Lotan reports a relationship with UTSW Simmons Comprehensive Cancer Center Tissue Management Shared Resource that includes: funding grants and nonfinancial support. Solomon Woldu. Consultant: Urogen Yair Lotan. Consultant: Nanorobotics, Photocure, Astra-Zeneca, Merck, Fergene, Abbvie, Nucleix, Ambu, Seattle Genetics, Hitachi, Ferring Research, verity pharmaceutics, virtuoso surgical, Stimit, Urogen, Vessi medical, CAPs medical, Xcures, BMS, Nonagen, Aura Biosciences, Inc., Convergent Genomics, Pacific Edge, Pfizer, Phinomics Inc, CG oncology, Uroviu, On target lab, Promis Diagnostics, Valar labs, Uroessentials, NRx Pharmaceuticals, Vesica health, Janssen, Immunity Bio If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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