Optimizing outcomes for high-risk, non-muscle-invasive bladder cancer: The evolving role of PD-(L)1 inhibition

Bedke, Jens; Black, Peter C.; Szabados, Bernadett; Guerrero-Ramos, Félix; Shariat, Shahrokh François; Xylinas, Evanguelos; Brinkmann, Julia; Blake-Haskins, John A; Cesari, Rossano; Redorta, Joan Palou

doi:10.1016/j.urolonc.2023.10.004

Cited by 4 publications

(1 citation statement)

References 83 publications

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“…Its main function is to down-regulate the immune response to humans' own cells, effectively preventing autoimmune reactions. Stimulating the PD-1/PD-L1 pathway is used by cancer cells to avoid immune response, allowing the progression of tumors [52]. BCG is a nonspecific immunotherapeutic, and combining it with an "immune checkpoint" inhibitor may give effective results even in BCG monotherapy-unresponsive tumors, especially if PD-L1 is present in tumor cells [53].…”

Section: Pembrolizumabmentioning

confidence: 99%

Revolutionizing Treatment: Breakthrough Approaches for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer

Jaromin,

Konecki,

Kutwin

2024

Cancers

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Bladder cancer is the 10th most popular cancer in the world, and non-muscle-invasive bladder cancer (NMIBC) is diagnosed in ~80% of all cases. Treatments for NMIBC include transurethral resection of the bladder tumor (TURBT) and intravesical instillations of Bacillus Calmette-Guérin (BCG). Treatment of BCG-unresponsive tumors is scarce and usually leads to Radical Cystectomy. In this paper, we review recent advancements in conservative treatment of BCG-unresponsive tumors. The main focus of the paper is FDA-approved medications: Pembrolizumab and Nadofaragene Firadenovec (Adstiladrin). Other, less researched therapeutic possibilities are also included, namely: N-803 immunotherapy, TAR-200 and TAR-210 intravesical delivery systems and combined Cabazitaxel, Gemcitabine and Cisplatin chemotherapy. Conservative treatment and delaying radical cystectomy would greatly benefit patients’ quality of life; it is undoubtedly the future of BCG-unresponsive NMIBC.

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Section: Pembrolizumabmentioning

confidence: 99%

Revolutionizing Treatment: Breakthrough Approaches for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer

Jaromin,

Konecki,

Kutwin

2024

Cancers

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Pharmacokinetics, safety, and efficacy of an alternative dosing regimen of sasanlimab in participants with advanced NSCLC and other malignancies

Penkov,

Bondarenko,

Saenko

et al. 2024

Ther Adv Med Oncol

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Background: Sasanlimab (PF-06801591), a humanized immunoglobulin G4 monoclonal antibody, binds to programmed cell death protein-1 (PD-1), preventing ligand (PD-L1) interaction. Objectives: To evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of two subcutaneous sasanlimab dosing regimens. Design: An open-label study consisting of phases Ib and II. Phase Ib: non-randomized, dose escalation, and expansion study in Asian participants with advanced malignancies. Phase II: conducted globally in participants with non-small-cell lung cancer with PD-L1 positive or PD-L1 status unknown tumors; participants were randomized 1:2 to receive subcutaneous sasanlimab 300 mg once every 4 weeks (300 mg-Q4W) or 600 mg once every 6 weeks (600 mg-Q6W). Methods: Primary endpoint in phase Ib: dose-limiting toxicity (DLT) occurring in first treatment cycle; in phase II: Ctrough and AUC. Results: A total of 155 participants (phase Ib, n = 34; phase II, n = 121) received sasanlimab. Phase Ib: no DLT reported. Phase II: ratio of adjusted geometric mean for AUCtau was 231.2 (90% CI, 190.1–281.2) and Ctrough was 111.5 (90% CI, 86.3–144.0) following 600 mg-Q6W (test) versus 300 mg-Q4W (reference). Phase Ib: grade 3 treatment-related adverse events (TRAEs) occurred in 1/4 (25%) and 3/12 (25%) participants treated in 300 mg-Q4W dose escalation and expansion cohorts, respectively. Phase II: grade 3 TRAEs occurred in 3/41 (7.3%) and 3/80 (3.8%) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively; no grade 4/5 TRAEs. Phase II: confirmed objective response was observed in 11/41 (26.8% (95% CI, 14.2–42.9)) and 12/80 (15.0% (95% CI, 8.0–24.7)) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively. Conclusions: Phase Ib regimens were considered safe with no DLTs reported. In phase II, 600 mg-Q6W regimen criteria were met for AUCtau and Ctrough metrics to support PK-based extrapolation of efficacy of alternative regimen. Regimens were well tolerated, showing anti-tumor activity in participants with advanced solid tumors. Administration of sasanlimab at a dose of 600 mg-Q6W subcutaneously may serve as a convenient alternative to 300 mg-Q4W administration. Trial registration: NCT04181788 (ClinicalTrials.gov); 2019-003818-14 (EudraCT).

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Update on the Mechanism of Action of Intravesical BCG Therapy to Treat Non-Muscle-Invasive Bladder Cancer

Abou Chakra,

Luo,

Duquesne

et al. 2024

Front. Biosci. (Landmark Ed)

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While more than four decades have elapsed since intravesical Bacillus Calmette-Guérin (BCG) was first used to manage non-muscle invasive bladder cancer (NMIBC), its precise mechanism of anti-tumor action remains incompletely understood. Besides the classic theory that BCG induces local (within the bladder) innate and adaptive immunity through interaction with multiple immune cells, three new concepts have emerged in the past few years that help explain the variable response to BCG therapy between patients. First, BCG has been found to directly interact and become internalized within cancer cells, inducing them to act as antigen-presenting cells (APCs) for T-cells while releasing multiple cytokines. Second, BCG has a direct cytotoxic effect on cancer cells by inducing apoptosis through caspase-dependent pathways, causing cell cycle arrest, releasing proteases from mitochondria, and inducing reactive oxygen species-mediated cell injury. Third, BCG can increase the expression of programmed death ligand 1 (PD-L1) on both cancer and infiltrating inflammatory cells to impair the cell-mediated immune response. Current data has shown that high-grade recurrence after BCG therapy is related to CD8+ T-cell anergy or ‘exhaustion’. High-field cancerization and subsequently higher neoantigen presentation to T-cells are also associated with this anergy. This may explain why BCG therapy stops working after a certain time in many patients. This review summarizes the detailed immunologic reactions associated with BCG therapy and the role of immune cell subsets in this process. Moreover, this improved mechanistic understanding suggests new strategies for enhancing the anti-tumor efficacy of BCG for future clinical benefit.

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Optimizing outcomes for high-risk, non-muscle-invasive bladder cancer: The evolving role of PD-(L)1 inhibition

Cited by 4 publications

References 83 publications

Revolutionizing Treatment: Breakthrough Approaches for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer

Revolutionizing Treatment: Breakthrough Approaches for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer

Pharmacokinetics, safety, and efficacy of an alternative dosing regimen of sasanlimab in participants with advanced NSCLC and other malignancies

Update on the Mechanism of Action of Intravesical BCG Therapy to Treat Non-Muscle-Invasive Bladder Cancer

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