Urologic Oncology: Seminars and Original Investigations
Review articleThe expanding repertoire of targets for immune checkpoint inhibition in bladder cancer: What lies beneath the tip of the iceberg, PD-L1
Section snippets
Historical perspective of immunotherapy for bladder cancer
The first suggestion of interplay between tumor biology and host immunity was in the 19th century when William Coley observed that infections were associated with tumor regression [1]. This antineoplastic effect of concomitant infection was again observed by Raymond Pearl at Johns Hopkins in 1929. He performed autopsies on patients who died of tuberculosis and noticed that there was a surprisingly low rate of underlying malignancy in these patients [2]. Alvaro Morales was the first to introduce
Overview of immune checkpoint receptors and pathways
Immune evasion is considered to be one of the hallmarks of cancer and is an essential step in the evolution of a tumor [13]. Tumor-immune evasion is achieved through multiple mechanisms: (1) selective evolution of tumors with down-regulated expression of neoantigens; (2) decrease or loss of expression of class I MHC molecules; (3) resistance to T-cell–mediated cytolytic killing; (4) presence of immune suppressing cells—regulatory T cells (T regs), myeloid-derived suppressor cells (MDSCs), and
Bladder tumors as immunogenic targets
Bladder cancers express high levels of PD-L1 [21]. Inman et al. demonstrated PD-L1 expression in bladder tumors of all stages, with particularly high levels in advanced stage tumors (30%) and tumors with carcinoma in situ (CIS) (45%). Furthermore, PD-L1 expression was abundant in tumors refractory to BCG treatment, suggesting that PD-L1 may play a role in shielding the tumor from immune-mediated tumor destruction. Boorjian et al. [22] observed that increased PD-L1 expression was associated with
Clinical trials of checkpoint inhibitors in urothelial carcinoma
Until 2016, there had been no new systemic treatments for advanced urothelial carcinoma approved by the FDA in 3 decades [12]. Recent clinical trials have demonstrated considerable therapeutic benefit of anti-CTLA-4 and anti-PD-1/PD-L1 agents in metastatic melanoma [24], [25], [26], leading to durable clinical remissions in an otherwise incurable disease.
The first phase I study of an anti-PD-L1 antibody (atezolizumab) in urothelial carcinoma was reported by Powles et al. [27]. Study
New immune checkpoints B7-H3, B7x, and HHLA2
The evolution of the B7 family members can be divided into 3 groups based on amino acid similarity. B7-H3 [35], B7x [36], [37], [38], and HHLA2 [39] form the third group of molecules [36] (Fig. 3). These molecules are widely expressed in many urologic malignancies, and their expression is associated with a poor prognosis [22], [40]. Tumor cell surface overexpression of these ligands is thought to play an essential role in suppressing T-cell response, leading to immune tolerance of malignancies.
Summary
The understanding of the regulation of T-cell activation and function along with the discovery of immune checkpoints with respect to the CD28 and B7 family has led to major advances scientifically and therapeutically in cancer. Clinical trials of agents targeting the PD-L1 checkpoint pathway have demonstrated durable clinical remissions in patients with otherwise untreatable advanced bladder cancer. Future studies should aim to further characterize the role of the newest B7 family molecules
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Cited by (8)
Checkpoint Genes at the Cancer Side of the Immunological Synapse in Bladder Cancer
2020, Translational OncologyCitation Excerpt :Still, most patients do not respond to single agent anti-PD1/PD-1L inhibition in BLCA, mandating a deeper understanding of the intricate immunological synapse in this disease. A recent review summarized the expanding repertoire of potential targets for immune modulation in the bladder and pointed out CD276, HHLA2, and VTCN1 as such [15]. Our results corroborate this review as well as previous research showing the CD276 mRNA and protein are expressed in BLCA [16] and contribute to the accumulating evidence of its role in BLCA.
Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial
2018, The LancetCitation Excerpt :Vinflunine (approved only in the European Union [EU]) and taxanes are commonly used,4,5 with prospective clinical data for these drugs showing a modest median overall survival of 6–7 months in this setting.6,7 In the past few years, checkpoint inhibitors have changed the treatment of metastatic urothelial carcinoma.8 In a randomised phase 3 trial,9 patients with metastatic urothelial carcinoma given pembrolizumab, an anti-programmed death-1 (PD-1) drug, had longer survival than did those given chemotherapy.
Atezolizumab in locally advanced or metastatic urothelial cancer: a pooled analysis from the Spanish patients of the IMvigor 210 cohort 2 and 211 studies
2021, Clinical and Translational Oncology
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A.S. is a consultant and advisor for Genentech. M.P.S. is an investor and consultant for Urogen.