Non-Muscle-Invasive Bladder Cancer: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Beatrix Zheng and Version 1 by Alessandro Audisio.

Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette–Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation.

  • non-muscle-invasive bladder cancer
  • BGC-unresponsive
  • immunotherapy
  • immune-checkpoint inhibitors
  • pembrolizumab

1. Immunotherapy in NMIBC: From BCG to the New Horizons of ICIs

1.1. BCG Administration Drives an Antitumour Innate and Adaptative Immune Response in NMIBC

BCG is a live attenuated strain of Mycobacterium bovis, its activity on NMIBC was firstly demonstrated by Morales and colleagues in 1976 [23][1]. The BCG mechanism of action is still not completely understood; however, it is known that BCG exposure of urothelium and bladder-resident macrophages elicits an inflammatory and immune response against tumoral cells [24,25,26][2][3][4]. The presumed mechanism is explicated in Figure 1.
Cells 11 00357 g001 550
Figure 1. BCG instillation elicits both innate and adaptative immune response against urothelial cancer cells. BCG, Bacillus Calmette–Guérin; DC, Dendritic Cell; IL, Interleukin; CXCL10, C-X-C motif Chemokine Ligand 10; GM-CSF, Granulocyte-Macrophage Colony-Stimulating Factor; CCL2, C-C Motif Chemokine Ligand 2; CCL3, C-C Motif Chemokine Ligand 3; PML, Polymorphonuclear Leukocytes; Th, Helper T cell; Treg, Regulatory T cell; Mϕ, Macrophage; CD8, Cluster of Differentiation 8; NK, Natural Killer; ROS, Reactive Oxygen Species; IFN-γ, Interferon-γ; TNF, Tumour Necrosis Factor.
The activation of antigen-presenting cells (APC) and urothelial cells following BCG internalization induces the release of several cytokines as Interleukin (IL)-1b, IL-8, IL-15, IL-18 and chemokine as CXC motif chemokine ligand 10 (CXCL10), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), CC-motif Chemokine ligand 2 (CCL2), and CCL3 activating the innate and adaptive immune response [27][5]. Local innate immunity activation leads to recruitment of macrophages, granulocytes, fibroblasts, dendritic cells, and lymphocytes, which form typical epithelioid and gigantocellular granulomas. In addition, neutrophils, Cluster of differentiation 8 (CD8) + T cells, and Natural Killer (NK) cells may have a direct antitumour effect, inducing the production of reactive oxygen species (ROS), antimicrobial enzymes and pro-apoptotic factors [28,29,30][6][7][8]. Concurrently, BCG causes the expression of the major histocompatibility complex (MHC) class II presenting BCG antigens on APC and urothelial cells driving the activation of adaptative immunity [31,32][9][10]. A prominent T Helper (TH) 1 cells-mediated immune response, associated with the secretion of IL-2, IL-12, Interferon (IFN)-γ, and Tumour Necrosis Factor (TNF) correlates with a response to BCG instillation. On the contrary, TH2 cells activation, characterized by the releasing of IL-4, IL-5, IL-6, and IL-10, is associated with an immunosuppressive microenvironment enrich of T regulatory cells (Treg), which is associated to a BCG-unresponsive state [24,33][2][11].
Several randomized controlled studies and large meta-analysis have clearly demonstrated that intravesical BCG after TURB, administered with an induction schedule of 6 weekly instillations, followed by additional maintenance every 3 to 6 months over 1 to 3 years is significantly superior compared to TURB alone or TURB followed by intravesical chemotherapy in NMIBC recurrence prevention. BCG treatment provides an high rate of CR in both patients with high-risk papillary tumours and with CIS and lowers tumour progression risk, representing the standard treatment for these patients [34][12].

1.2. PD-L1 and PD-1 Expression Is Associated to BCG Immune-Resistance

The main resistance mechanism to BCG treatment is linked to an intrinsic or an acquired immune resistance. The interaction of PD-1, expressed by T cells, with its ligand Programmed Death-Ligand 1 (PD-L1), normally expressed by a subset of macrophages and inducible on activated T, B and NK cells, endothelial cells, and other non-malignant cells in an inflammatory milieu is a major immune checkpoint pathway involved in immune homeostasis, down-regulating T cell response in case of chronic antigen exposure. Cancer-related overexpression of PD-L1 lets cancer cells to evade immune response, inducing T cell anergy. The use of PD-1 or PD-L1-directed mAb, can prevent their interaction and restore T cell activity against cancer cells [35,36][13][14].
Kates and colleagues showed in an analysis on tissue microarrays of paired pre- and post-BCG bladder samples that BCG-unresponders patients had in 25–30% of cases a pre-treatment enrichment of PD-L1 + cells, high density of CD8+ T cells, and lacked of CD4+ T cells. On the contrary, PD-L1 expression was nearly absent among BCG responders [37][15]. Pierconti et al. confirmed these results. PD-L1 expression in tumour cells and in immune cells was higher in BCG-unresponsive CIS patients than in BCG-responders, suggesting that PD-L1 expression could help to identify CIS that would fail BCG therapy [38][16]. In addition, BCG treatment could enhance PD-L1 and PD-1 expression. Hashizume et al. observed that PD-L1 expression levels increased after BCG. Similarly, Fukumoto et al., testing PD-1 staining in a cohort of NMIBC treated with BCG, found that PD-1 expression was superior in BCG-unresponsive tumors compared with pretreatment tumors from the same patients, hypothesizing that BCG could induce this immune checkpoint. Furthermore, PD-1 expression was correlated with worse clinical outcomes [39,40][17][18]. BCG instillation seems to induce the expression of PD-L1 in tumour and inflammatory cells trough the induction of CD8+ T cells, which are the major responsible of IFN-γ production [39][17]. Chevalier and colleagues reported an increasing number of PD-L1-expressing CD4+ T cells (PD-L1+ Tregs) in BCG-resistant patients [41][19], while Copland et al. demonstrated that BCG treatment causes the up-regulation of PD-L1 expression on APCs inducing the secretion of some cytokines as Il-6, IL-10, leading to STAT3 phosphorylation and ultimately PD-L1 expression [42][20].

1.3. ICIs for the Treatment of Advanced Urothelial Cancer

The high tumoral mutational burden (TMB) of urothelial cancer, similar to melanoma and non-small-cell lung cancer, and the expression of immune checkpoint PD-1 and PD-L1 both by immune cells and microenvironmental cells constitute the biological rational for the activity of ICIs in bladder cancer [43,44][21][22]. Nowadays ICIs represent the standard second-line therapy in patients with advanced or metastatic urothelial cancer who progressed on first-line platinum-based chemotherapy. Pembrolizumab, an anti-PD-1 mAb, according to results of phase III trial KEYNOTE-045 is the preferred option [45,46][23][24]. First-line immunotherapy does not provide a statistical significant survival benefit compared to platinum-based chemotherapy, even when it was given in association; however, avelumab, an anti-PD-L1 monoclonal IgG, as maintenance in patients who did not have disease progression with first-line chemotherapy, gets the approval on the basis of JAVELIN Bladder 100 [46,47][24][25]. Moreover, nivolumab, another PD-1 mAb was recently granted FDA approval for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after RC on the basis of results of CheckMate-274, and several trials are investigating the role of ICIs in neoadjuvant and perioperative setting [46,48][24][26]. Clinical or biological markers predictive of response are still lacking; however, PD-L1 expression and elevated TMB status seem to be correlated with an increased response rate [49][27].

1.4. ICIs Activity in BCG-Unresponsive NMIBC

The enhanced immune checkpoint expression shown in BCG-unresponsive patients and the efficacy of ICIs in advanced BC represented the rationale for testing them in NMIBC. Pembrolizumab was investigated in the phase II KEYNOTE-057 trial (Table 1). In the cohort A of the study, intravenous pembrolizumab was administered for up to 24 months in patients with BCG-unresponsive CIS patients, who resulted ineligible or declines RC. After a median follow-up of 36.4 months, 41% of patients (95% CI 30.7–51.1%) achieved a CR assessed by cystoscopy and urine cytology. Eleven of 39 patients with CR (28%) were disease-free at data cut-off analysis. Results of the study cohort B, which enrolled patients with BCG-unresponsive NMIBC without CIS, have not been published yet. Safety profile was consistent with other studies testing pembrolizumab; serious treatment-related adverse events (G3 or G4 according to World Health Organization, WHO) were rare [19][28]. On the basis of these results, in January 2020, FDA approved pembrolizumab for the treatment of patients with BCG-unresponsive CIS who are ineligible for or who decline RC [19][28].
Table 1. Key positive clinical trials enrolling patients with BCG-unresponsive NMIBC.
Agent/

Target		NCT/

Acronym		PhasePrimary EndpointPatients EnrolledMedian Follow UpResults
Pembrolizumab *

ICI

Anti-PD1 IgG4/kappa		NCT02625961

KEYNOTE-057

[28]		IICRR of high-risk NMIBCCohort A (CIS): 101 pts

Cohort B (Non-CIS): 47 pts		36.4 mos.Cohort A: 41% (39 out of 96 pts, 95% CI 30.7–51.1%)
Atezolizumab

Atezolizumab was tested in the phase II SWOG S1605 trial (Table 1). One hundred and thirty-five patients with BCG-unresponsive NMIBC were enrolled, 70 of them had been diagnosed with CIS, and atezolizumab was given them every 3 weeks up to complete one year of treatment. Thirty patients had a CR at 3 months (41.1%; 95% CI 29.7–53.2%) and 19 at 6 months (26.0%; 95% CI 16.5–37.6%) [50][32]. In the overall population, 29 patients (29%; 90% CI 22–36%) were free of recurrence or progression at 18 months, the percentage of event-free survival was greater in non-CIS patients than in CIS patients. The treatment was globally well tolerated. Serious grade adverse events occurred in 17% of patients and there were two treatment-related deaths [20][29].
Several clinical trials are now ongoing testing different ICIs in BCG-unresponsive NMIBC (Table 2). Durvalumab, an anti-PD-L1 Immunoglobulin G1 (IgG1) mAb, camrelizumab, an anti PD-1 ICI, and HX008 (pucotenlimab), a new recombinant anti-PD-1 monoclonal IgG4 are being tested as monotherapy respectively in NCT04738630, NCT04706598, NCT03759496. ADAPT-BLADDER study (NCT03317158) is investigating durvalumab activity in association with radiotherapy, while PREVERT trial (NCT03950362) activity of avelumab. Durvalumab is, furthermore, being evaluated in association with an anti-CTLA4 mAb, tremelimumab in RIDEAU study (NCT05120622). SunRISe-1 study (NCT04640623) endpoints are to assess the efficacy and safety of TAR-200, an intravesical gemcitabine-delivery system, in association with an anti PD-1 mAb, cetrelimab, or of these two drugs alone in BCG-unresponsive high-risk NMIBC. NCT04164082 trial investigates the combination of pembrolizumab and gemcitabine.
Table 2. Ongoing clinical trials testing ICIs (in bold font) alone or in combination in NMIBC.
Ongoing clinical trials testing ICIs (in bold font) alone or in combination in NMIBC.
NCT/AcronymStatusPhaseDrug(s)ControlPrimary Endpoints
Cells 11 00357 g002 550
Figure 2. Main targets of novel drugs being investigated in BCG-unresponsive NMIBC. TPH, Tryptophan; KYN, Kynurenine; IFNα2b, Interferon α2b; DC, Dendritic Cell; PD1, Programmed cell Death protein 1; PD-L1, Programmed Death-Ligand 1; mAb, monoclonal Antibody; GM-CSF, Granulocyte-Macrophage Colony-Stimulating Factor; FGFR, Fibroblast Growth Factor Receptor; TKI, Tyrosine Kinase Inhibitors; IDO1, Indoleamine 2,3-Dioxygenase 1; IL-15Rα, Interleukin-15 receptor α; MHCII, Major Histocompatibility Complex Class II; TCR, T Cell Receptor; TLR7, Toll-like Receptor 7; EpCAM, Epithelial Cell Adhesion Molecule; CD3, Cluster of Differentiation 3.
Table 3. Clinical trials testing novel or emerging drugs (in bold font) alone or in combination in NMIBC.
NCT/AcronymStatusPhaseDrug(s)Target or MechanismPrimary Endpoints
ICI


Anti-PD-L1 IgG1		NCT02844816
(a) BCG-unresponsive or BCG-intolerant NMIBC

SWOG S1605

[29]		IICRR at 25 weeks in CIS-cohort
(a) BCG-unresponsive or BCG-intolerant NMIBC
NCT05014139CIS cohort: 70 pts pre-planned Non-CIS cohort: 65 pts pre-planned
NCT05120622

Rideau		Recruiting1, 2Durvalumab, tremelimumabNot yet recruiting—NRCIS cohort: 27% (20 out of 74 pts, 95% CI NR)
TRAEs, MTDNadofaragene firadenovec

rAd-IFNa2b/Syn3		NCT02773849 [30]IIICRR at 12 mos. in CIS-cohortCIS-cohort: 107 pts

Non-CIS cohort: 50 pts		19.7 mos.CIS-cohort: 53.4% (55 out of 103 patients, 95% CI 43.3–63.3%)
NCT04738630Recruiting2HX008 (Pucotenlimab)—CRR, EFSOportuzumab Monatox

EpCAM scFv linked to ETA		NCT02449239 [31]IIICRR in CIS-cohort126 pts

CIS-cohort: 89 pts		NRCIS-cohort: 40% (95% CI NR)
* FDA approved. NCT, Number Clinical Trial; ICI, Immune Checkpoint Inhibitor; PD1, Programmed cell Death protein-1; IgG, Immunoglobulin G; CRR, Complete Response Rate; NMIBC, Non-Muscle-Invasive Bladder Cancer; CIS, Carcinoma In Situ; mos., months; pts, patients; PD-L1, Programmed death-Ligand 1; NR, Not reported; rAd-IFNa2b, non-replicating recombinant adenovirus type 5 (Ad5)-vector encoding the interferon alpha-2b; EpCAM, Epithelial Cell Adhesion Molecule; scFv, single-chain Fragment variable; ETA, Pseudomonas exotoxin A; BCG, Bacillus Calmette–Guérin.
 
1
Enfortumab Vedotin
ADC against Nectin-4TRAEs, DLT
NCT04917809Not yet recruiting2ErdafitinibFGFR-TKIORRNCT04706598
NCT04799847RecruitingNot yet recruiting1, 21, 2CamrelizumabCatumaxomab—Bispecific (anti-EpCAM, anti-CD3) AbMTD, RFS
DLT, TRAEsNCT04640623 SunRISe-1Recruiting2TAR-200, CetrelimabTAR-200 or CetrelimabCRR
NCT04498702Completed2APL-1202MetAP2 inhibitorRFRNCT04387461

CORE-001		Recruiting2CG0070, Pembrolizumab—CRR
NCT04452591

BOND-003		Recruiting3CG0070Oncolytic adenovirusCRRNCT04164082Recruiting2Pembrolizumab, gemcitabine—CRR in CIS subpopulation, EFS
NCT04172675Recruiting2Erdafitinib vs. gemcitabine/MMCFGFR-TKIRFSNCT03950362 PREVERTNot yet recruiting2Avelumab, RDT—RFS
NCT03914794Recruiting2PemigatinibFGFR1-3-TKICRRNCT03759496
NCT03022825

Recruiting		2Durvalumab—MTD, RFS
QUILT-3.032Recruiting2, 3BCG, ALT-803IL-15 superagonistCRR, DFRNCT03519256

CheckMate 9UT		Active, not recruiting2Nivolumab, BMS-986205 (Linrodostat mesylate)NivolumabCRR, DoR
NCT03317158

ADAPT-BLADDER		Recruiting1, 2
NCT02009332Completed1, 2Nab-sirolimus, gemcitabinemTOR inhibitorDLT, CRRDurvalumab, RDT—RP2D, RFS
NCT01731652Completed2VesimuneTLR-7 agonistCRRNCT04149574

CheckMate 7G8		Recruiting3Nivolumab, BCG
NCT02371447Active, not recruiting1, 2BCGVPM1002BCEFS
Modified BCGDLT, RFRNCT04106115

DURANCE		Not yet recruiting1, 2Durvalumab, S-488210/S-488211 vaccine—DLT, DFSR
NCT03892642

(b) BCG-naïve NMIBCABC TrialActive, not recruiting1, 2Avelumab, BCG—DLT
NCT04736394

ASCERTAIN		Not yet recruiting(b) BCG-naïve NMIBC
3APL-1202 vs. epirubicinMetAP2 inhibitorNCT04922047

TACBIN-01		Recruiting1, 2Tislelizumab, BCG—DLT
EFS
NCT02138734Recruiting1, 2ALT-803, BCGIL-15 superagonistCRR, DFSNCT04730232Recruiting2Tislelizumab, nab-paclitaxel—CRR
NCT04165317 *

CREST		Recruiting3Sasanlimab, BCGBCGEFS, CRR
NCT03799835

ALBAN		Recruiting3Atezolizumab, 1y BCGBCGRFS
NCT03711032 *

KEYNOTE-676		Recruiting3Pembrolizumab, BCGBCGCRR, EFS
NCT03528694

POTOMAC		Active, not recruiting3Durvalumab, BCGBCGDFS
(a) Enrolling patients with BCG-unresponsive or BCG-intolerant NMIBC. (b) Enrolling patients with BCG-naïve NMIBC. * Enrolling patient with either BCG-unresponsive or BCG-naïve NMIBC. NCT, Number Clinical Trial; BCG, Bacillus Calmette–Guérin; NMIBC, Non-Muscle-Invasive Bladder Cancer; TRAEs, Treatment-Related Adverse Events; MTD, Maximum Tolerated Dose; CRR, Complete Response Rate; EFS, Event-Free Survival; RFS, Recurrence-Free Survival; CIS, Carcinoma In Situ; RP2D, Recommended phase 2 dose; DLT, Dose-Limiting Toxicity.
 
As explicated before, BCG-resistance could be linked to an immunosuppressive state induced by the expression of immune checkpoint, and BCG itself could enhance PD-1 and PD-L1; this provides the grounds for trials that are testing anti-PD1 or anti-PD-L1 antibodies in association with BCG as front-line therapy in NMIBC in BCG-naïve patients or in patients not reaching a CR after BCG induction (Table 2). KEYNOTE-676 (NCT03711032) is a phase III trial assessing pembrolizumab activity in combination with BCG in patients with persistent high-risk NMIBC after BCG induction. CheckMate 7G8 (NCT04149574) and POTOMAC (NCT03528694) studies testing respectively nivolumab and durvalumab have a similar design. NCT03892642 is a phase I/II trial planned to evaluate BCG in association with avelumab as induction treatment. The primary endpoint of the phase I of the trial was the completion of a full induction course. The primary endpoint was reached, the combination of BCG with an ICI was reported to be safe and well tolerated, and phase II is still ongoing [51][33]. The NCT04730232 study is testing tislelizumab in association with nab-paclitaxel chemotherapy, while in the DURANCE trial (NCT04106115), it is in combination with S-488210/S-488211, a cancer multi-peptide vaccine able to stimulate a cytotoxic T cell (CTL) response against urothelial cancer cells [52][34].

2. Alternative Targets: The Way to Develop New Effective Drugs

The deep improvement in the knowledge regarding the biological mechanisms responsible for neoplastic cells progression and BCG resistance mechanisms has led to identification of new targets (Figure 2); consequently, several innovative agents were developed and are now under investigation in the treatment of NMIBC (Table 3).
(a) Enrolling patients with BCG-unresponsive or BCG-intolerant NMIBC. (b) Enrolling patients with BCG-naïve NMIBC. NCT, Number Clinical Trial; BCG, Bacillus Calmette–Guérin; NMIBC, Non-Muscle-Invasive Bladder Cancer; ADC, Antibody-Drug Conjugate; TRAEs, treatment-related Adverse Events; DLT, Dose-Limiting Toxicity; MMC, Mitomycin C; FGFR, Fibroblast Growth Factor-receptor; TKI, Tyrosine Kinase Inhibitor; ORR, Objective Response Rate; EpCAM, Epithelial Cell Adhesion Molecule; CD3, Cluster of Differentiation 3; Ab, Antibody; MetAP2, Methionyl Aminopeptidase 2; RFR, Recurrence-free Rate; CRR, Complete Response Rate; RFS, Recurrence-Free Survival; IL-15, Interleukin-15; DFR, Disease-Free Rate; mTOR, Mammalian Target of Rapamycin; TLR-7, Toll-Like Receptor 7; EFS, Event-Free Survival.

References

  1. Morales, A.; Eidinger, D.; Bruce, A.W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol. 1976, 116, 180–182.
  2. Larsen, E.S.; Joensen, U.N.; Poulsen, A.M.; Goletti, D.; Johansen, I.S. Bacillus Calmette–Guérin immunotherapy for bladder cancer: A review of immunological aspects, clinical effects and BCG infections. Apmis 2020, 128, 92–103.
  3. Ingersoll, M.A.; Albert, M.L. From infection to immunotherapy: Host immune responses to bacteria at the bladder mucosa. Mucosal Immunol. 2013, 6, 1041–1053.
  4. Teppema, J.S.; de Boer, E.C.; Steerenberg, P.A.; van der Meijden, A.P. Morphological aspects of the interaction of Bacillus Calmette-Guérin with urothelial bladder cells in vivo and in vitro: Relevance for antitumor activity? Urol. Res. 1992, 20, 219–228.
  5. Bisiaux, A.; Thiounn, N.; Timsit, M.-O.; Eladaoui, A.; Chang, H.-H.; Mapes, J.; Mogenet, A.; Bresson, J.-L.; Prié, D.; Béchet, S.; et al. Molecular analyte profiling of the early events and tissue conditioning following intravesical bacillus calmette-guerin therapy in patients with superficial bladder cancer. J. Urol. 2009, 181, 1571–1580.
  6. Ludwig, A.T.; Moore, J.M.; Luo, Y.; Chen, X.; Saltsgaver, N.A.; O’Donnell, M.A.; Griffith, T.S. Tumor necrosis factor-related apoptosis-inducing ligand: A novel mechanism for Bacillus Calmette-Guérin-induced antitumor activity. Cancer Res. 2004, 64, 3386–3390.
  7. Lage, J.M.; Bauer, W.C.; Kelley, D.R.; Ratliff, T.L.; Catalona, W.J. Histological parameters and pitfalls in the interpretation of bladder biopsies in bacillus Calmette-Guerin treatment of superficial bladder cancer. J. Urol. 1986, 135, 916–919.
  8. Mitropoulos, D.N. Novel insights into the mechanism of action of intravesical immunomodulators. In Vivo 2005, 19, 611–621.
  9. Stefanini, G.F.; Bercovich, E.; Mazzeo, V.; Grigioni, W.F.; Emili, E.; D’Errico, A.; Lo Cigno, M.; Tamagnini, N.; Mazzetti, M. Class I and class II HLA antigen expression by transitional cell carcinoma of the bladder: Correlation with T-cell infiltration and BCG treatment. J. Urol. 1989, 141, 1449–1453.
  10. Ikeda, N.; Toida, I.; Iwasaki, A.; Kawai, K.; Akaza, H. Surface antigen expression on bladder tumor cells induced by bacillus Calmette-Guérin (BCG): A role of BCG internalization into tumor cells. Int. J. Urol. 2002, 9, 29–35.
  11. Luo, Y. Blocking IL-10 enhances bacillus Calmette-Guérin induced T helper Type 1 immune responses and anti-bladder cancer immunity. Oncoimmunology 2012, 1, 1183–1185.
  12. Pettenati, C.; Ingersoll, M.A. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat. Rev. Urol. 2018, 15, 615–625.
  13. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264.
  14. Topalian, S.L.; Taube, J.M.; Anders, R.A.; Pardoll, D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 2016, 16, 275–287.
  15. Kates, M.; Matoso, A.; Choi, W.; Baras, A.S.; Daniels, M.J.; Lombardo, K.; Brant, A.; Mikkilineni, N.; McConkey, D.J.; Kamat, A.M.; et al. Adaptive immune resistance to intravesical BCG in non–muscle invasive bladder cancer: Implications for prospective BCG-unresponsive trials. Clin. Cancer Res. 2020, 26, 882–891.
  16. Pierconti, F.; Raspollini, M.R.; Martini, M.; Larocca, L.M.; Bassi, P.F.; Bientinesi, R.; Baroni, G.; Minervini, A.; Petracco, G.; Pini, G.M.; et al. PD-L1 expression in bladder primary in situ urothelial carcinoma: Evaluation in BCG-unresponsive patients and BCG responders. Virchows Arch. 2020, 477, 269–277.
  17. Hashizume, A.; Umemoto, S.; Yokose, T.; Nakamura, Y.; Yoshihara, M.; Shoji, K.; Wada, S.; Miyagi, Y.; Kishida, T.; Sasada, T. Enhanced expression of PD-L1 in non-muscle-invasive bladder cancer after treatment with Bacillus Calmette-Guerin. Oncotarget 2018, 9, 34066–34078.
  18. Fukumoto, K.; Kikuchi, E.; Mikami, S.; Hayakawa, N.; Matsumoto, K.; Niwa, N.; Oya, M. Clinical Role of Programmed Cell Death-1 Expression in Patients with Non-muscle-invasive Bladder Cancer Recurring After Initial Bacillus Calmette–Guérin Therapy. Ann. Surg. Oncol. 2018, 25, 2484–2491.
  19. Chevalier, M.F.; Schneider, A.K.; Cesson, V.; Dartiguenave, F.; Lucca, I.; Jichlinski, P.; Nardelli-Haefliger, D.; Derré, L. Conventional and PD-L1-expressing Regulatory T Cells are Enriched During BCG Therapy and may Limit its Efficacy. Eur. Urol. 2018, 74, 540–544.
  20. Copland, A.; Sparrow, A.; Hart, P.; Diogo, G.R.; Paul, M.; Azuma, M.; Reljic, R. Bacillus Calmette-Guérin Induces PD-L1 Expression on Antigen-Presenting Cells via Autocrine and Paracrine Interleukin-STAT3 Circuits. Sci. Rep. 2019, 9, 3655.
  21. Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Aparicio, S.A.J.R.; Behjati, S.; Biankin, A.V.; Bignell, G.R.; Bolli, N.; Borg, A.; Børresen-Dale, A.L.; et al. Signatures of mutational processes in human cancer. Nature 2013, 500, 415–421.
  22. Samstein, R.M.; Lee, C.-H.; Shoushtari, A.N.; Hellmann, M.D.; Shen, R.; Janjigian, Y.Y.; Barron, D.A.; Zehir, A.; Jordan, E.J.; Omuro, A.; et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 2019, 51, 202–206.
  23. Bellmunt, J.; de Wit, R.; Vaughn, D.J.; Fradet, Y.; Lee, J.-L.; Fong, L.; Vogelzang, N.J.; Climent, M.A.; Petrylak, D.P.; Choueiri, T.K.; et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N. Engl. J. Med. 2017, 376, 1015–1026.
  24. Roviello, G.; Catalano, M.; Santi, R.; Palmieri, V.E.; Vannini, G.; Galli, I.C.; Buttitta, E.; Villari, D.; Rossi, V.; Nesi, G. Immune checkpoint inhibitors in urothelial bladder cancer: State of the art and future perspectives. Cancers 2021, 13, 4411.
  25. Powles, T.; Park, S.H.; Voog, E.; Caserta, C.; Valderrama, B.P.; Gurney, H.; Kalofonos, H.; Radulović, S.; Demey, W.; Ullén, A.; et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N. Engl. J. Med. 2020, 383, 1218–1230.
  26. Bajorin, D.F.; Witjes, J.A.; Gschwend, J.E.; Schenker, M.; Valderrama, B.P.; Tomita, Y.; Bamias, A.; Lebret, T.; Shariat, S.F.; Park, S.H.; et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N. Engl. J. Med. 2021, 384, 2102–2114.
  27. Rosenberg, J.E.; Hoffman-Censits, J.; Powles, T.; van der Heijden, M.S.; Balar, A.V.; Necchi, A.; Dawson, N.; O’Donnell, P.H.; Balmanoukian, A.; Loriot, Y.; et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 2016, 387, 1909–1920.
  28. Balar, A.V.; Kamat, A.M.; Kulkarni, G.S.; Uchio, E.M.; Boormans, J.L.; Roumiguié, M.; Krieger, L.E.M.; Singer, E.A.; Bajorin, D.F.; Grivas, P.; et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): An open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021, 22, 919–930.
  29. Black, P.C.; Tangen, C.; Singh, P.; McConkey, D.J.; Lucia, S.; Lowrance, W.T.; Koshkin, V.S.; Stratton, K.L.; Bivalacqua, T.; Kassouf, W.; et al. Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816). J. Clin. Oncol. 2021, 39, 4541.
  30. Boorjian, S.A.; Alemozaffar, M.; Konety, B.R.; Shore, N.D.; Gomella, L.G.; Kamat, A.M.; Bivalacqua, T.J.; Montgomery, J.S.; Lerner, S.P.; Busby, J.E.; et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: A single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021, 22, 107–117.
  31. Shore, N.; O’Donnell, M.; Keane, T.; Jewett, M.A.; Kulkarni, G.S.; Dickstein, R.; Wolk, F.; Dunshee, C.; Belkoff, L.; Dillon, R.L.; et al. PD03-02 Phase 3 results of Vicineum in BCG-unresponsive Non-Muscle Invasive Bladder Cancer. J. Urol. 2020, 203, e72.
  32. Black, P.C.; Tangen, C.; Singh, P.; McConkey, D.J.; Lucia, S.; Lowrance, W.T.; Koshkin, V.S.; Stratton, K.L.; Bivalacqua, T.; Sharon, E.; et al. Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816). J. Clin. Oncol. 2020, 38, 5022.
  33. Michael, C.; Abhishek, T.; Sanjay, P.; Daniel, Z.; Yuejin, W.; Riza, F.; Kelly, S. LBA02-04 Novel weekly immunotherapy dosing with avelumab tolerated during Bacillus Calmette-Guerin induction therapy: Initial results of the ABC trial. J. Urol. 2021, 206, e1177.
  34. Definition of Multipeptide Vaccine S-588210—NCI Drug Dictionary—National Cancer Institute. Available online: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/multipeptide-vaccine-s-588210 (accessed on 23 November 2021).
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback