Novel immunotherapeutic options for BCG-unresponsive high-risk non-muscle-invasive bladder cancer

Abstract

Background: High-risk non-muscle-invasive bladder cancer (HR-NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette-Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle-invasive bladder cancer (MIBC). Patients who are BCG-unresponsive have worse prognosis and thus require further management including radical cystectomy (RC), which significantly impacts quality of life. Moreover, the ongoing worldwide shortage of BCG warrants the need for policies that prioritize drug use and utilize alternative treatment strategies. Hence, there is a significant unmet need for bladder preserving therapy in this subset of patients.

Methods: To address this issue, we searched the relevant literature in PUBMED for articles published from 2019 through May of 2023 using appropriate keywords. All clinical trials of patients with HR-NMIBC treated with immune-related agents were retrieved from clinicaltrials.gov.

Findings and future perspectives: Exploratory treatments for BCG-Unresponsive HR-NMIBC included immune checkpoint inhibitors (ICI), oncolytic viral therapy, cytokine agonists, and other immunomodulators targeting TLR, EpCaM, FGFR, MetAP2, and IDO1. Some combination therapies have been found to work synergistically and are preferred therapeutically over monotherapy. Three drugs-pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec-vncg-have been FDA approved for the treatment of BCG-unresponsive NMIBC in patients who are ineligible for or decline RC. However, all explored treatment options tend to postpone RC rather than provide long-term disease control. Additional combination strategies need to be studied to enhance the effects of immunotherapy. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR-NMIBC is essential for the discovery of new targets and the development of effective treatments.

Keywords: Bacillus Calmette-Guérin-unresponsive; gene therapy; immune checkpoint inhibitors; immunotherapy; non-muscle-invasive bladder cancer; oncolytic viral therapy; targeted therapy.

FIGURE 1

Interplay between Bacillus Calmette–Guérin (BCG) and immune‐checkpoint inhibitors in non‐muscle‐invasive bladder cancer. BCG acts through innate and adaptive immune responses to induce anti‐tumor activity. Programmed cell death‐1 (PD‐1) and cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) interact with their ligands programmed cell death‐ ligand 1 PD‐L1 and CD80/88, respectively, to predominantly suppress T‐cell response., Patients with increased PD‐1 and PD‐L1 expression in the tumor microenvironment tend to be BCG‐unresponsive due to enhanced tumor immune evasion., Immune checkpoint inhibitors counteract immune escape mechanisms of bladder tumor cells by targeting PD‐1, PD‐L1, and CTLA‐4. Anti‐PD‐1, anti‐PD‐L1, and anti‐CTLA‐4 agents that have been used in clinical trials for high‐risk non‐muscle‐invasive bladder cancer are written in boxes. Lymphocyte‐activation gene 3 (LAG‐3), which binds to major histocompatibility complex class II (MHC ll), and T‐cell immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain (TIGIT),, , which binds to binds to CD112/155, are other suggested immune checkpoints that are yet to show results in clinical trials involving this subset of patients. BCG, Bacillus Calmette–Guérin; CTLA‐4, cytotoxic T‐lymphocyte antigen 4; DC, dendritic cells; LAG‐3, lymphocyte‐activation gene 3; MHC II, major histocompatibility complex class II; NK, natural killers; PD‐1, programmed cell death‐1; PD‐L1, programmed cell death ligand 1; PML, polymorphonuclear leukocytes; TIGIT, T‐cell immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain.

FIGURE 2

Alternative therapeutic options in high‐risk non‐muscle‐invasive bladder cancer. Nadofaragene firadenovec‐vcng and CG0070 are adenoviral carriers of cDNA encoding IFN‐α2b and GM‐CSF, respectively. CG0070 exploits tumoral cell faulty retinoblastoma pathway. EG‐70 binds to retinoic acid‐inducible gene‐1 (RIG‐1) to produce IFNα/β and increases levels of IL‐12., Both interferons and IL‐12 activate CD8⁺ T‐cells and natural killers (NK), resulting in release of cytotoxic perforins and granzymes., Catumaxomab and oportuzumab monatox target EpCaM, releasing exotoxin A., Imiquimod acts as TLR‐7 agonist that reduces tumorigenesis and boosts BCG effects through upregulation of TLR‐4 and 7. Mutations in fibroblast growth factor receptor (FGFR) kinase and methionine aminopeptidases 2 (MetAP2) promote tumorigenesis., , Whereas, increased indoleamine‐2,3‐dioxygenase 1 (IDO‐1) enzyme expression enhances immune tolerance. Linrodostat and APL‐1201 are inhibitors of IDO‐1 and MetAP2 receptors, respectively. Erdafitinib inhibits FGFR kinase, and ALT‐803 binds to IL‐15 receptor α subunit, releasing IL‐15 which acts on CD8⁺ T‐cells and NKs. BCG, Bacillus Calmette–Guérin; EpCaM, epithelial cell adhesion molecule; FGFR, fibroblast growth factor receptor; GM‐CSF, granulocyte‐macrophage colony stimulating factor; IDO‐1, indoleamine‐2,3‐dioxygenase 1; IFN, interferon; IL, interleukin; MetAP2, methionine aminopeptidases 2; NK, natural killer; RIG‐1, retinoic acid‐inducible gene‐1; TLR, toll‐like receptor.