New Strategies in Bladder Cancer: A Second Coming for Immunotherapy

Ghasemzadeh, Ali; Bivalacqua, Trinity J.; Hahn, Noah M.; Drake, Charles G.

doi:10.1158/1078-0432.ccr-15-1135

Cited by 61 publications

(35 citation statements)

References 91 publications

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“…Agonists that activate T cells via costimulatory molecules could be combined with BCG; one such molecules is OX40, a cell surface molecule which serves as a potent costimulatory signal to effector T cells, and is in phase I trials in patients with advanced cancer (NCT02219724) (32, 33). Similarly, 4-1BB is another costimulatory molecule expressed on activated T cells being studied in human cancer trials (NCT02111863), which—leads to increased proliferation of anti-apoptotic molecules on lymphocytes (34).…”

Section: Discussionmentioning

confidence: 99%

Intravesical BCG Induces CD4+ T-Cell Expansion in an Immune Competent Model of Bladder Cancer

Kates¹,

Nirschl

Sopko³

et al. 2017

Cancer Immunology Research

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Intravesical BCG immunotherapy is the standard of care in treating non-muscle invasive bladder cancer, yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. Although prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T-cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Our data demonstrate that cancer progression in the MNU rat model of bladder cancer was characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. In contrast, treatment with intravesical BCG led to a large, transient rise in the CD4+ T-cell population in the urothelium, and was both more effective and immunogenic compared to intravesical chemotherapy. Whole transcriptome expression profiling of post-treatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that although BCG induces T-cell recruitment to the bladder, the T-cell phenotype does not markedly change, implying that combining T-cell activating agents with BCG might improve clinical activity.

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Section: Discussionmentioning

confidence: 99%

Intravesical BCG Induces CD4+ T-Cell Expansion in an Immune Competent Model of Bladder Cancer

Kates¹,

Nirschl

Sopko³

et al. 2017

Cancer Immunology Research

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“…The known receptor for PD-L1 is PD-1, a key immunosuppressive marker expressed on exhausted TIL, which may be responsible for the poor outcome of higher CD8 ST + TIL density for UCB patients. 28 To test the hypothesis, distribution and clinical significance of PD-1 + TIL were examined. PD-1 + TIL were more frequent in ST than in INT (12 ± 1 and 4 ± 1 cells/field, respectively; Figure 5A,B; n = 82).…”

Section: Associations Between Pd-1 + Til and Pd-l1 + Ic Cd8 + Til mentioning

confidence: 99%

Programmed death ligand‐1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder

et al. 2018

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Drugs blocking programmed death ligand‐1 (PD‐L1) have shown unprecedented activity in metastatic and unresectable bladder cancer. The purpose of the present study was to investigate the expression, clinical significance and association of PD‐L1 with tumor‐infiltrating lymphocytes (TIL) in resectable urothelial cell carcinoma of the bladder (UCB). In this retrospective study, 248 UCB patients who received radical cystectomy or transurethral resection were examined. Immunohistochemistry was used to evaluate PD‐L1 expression and stromal CD8+ TIL, Th1 orientation T cell (T‐bet+) and PD‐1+ TIL densities within the intratumoral regions and associated stromal regions. Of the 248 specimens, 23% showed PD‐L1 expression in tumor cells and 55% in tumor‐infiltrating immune cells. CD8+ TIL, T‐bet+ TIL and PD‐1+ TIL were distributed throughout the tumor tissues and were more frequently distributed in stromal regions than in intratumoral regions. PD‐L1+ tumor cells and PD‐L1+ immune cells were positively associated with aggressive clinical features (all P < .05). Both PD‐L1+ tumor cells and PD‐L1+ immune cells were associated with poorer recurrence‐free and overall survival (all P < .05). Multivariate analysis showed that PD‐L1+ immune cells were an independent prognostic factor for overall (P = .001) and recurrence‐free survival (P = .024). Notably, high stromal CD8+ TIL and PD‐1+ TIL density were associated with poorer overall survival (P = .031 and P = .001, respectively). In the stroma, CD8+ TIL density has strong positive association with PD‐L1+ immune cells and PD‐1+ TIL density (all P < .0001). These results suggested that an exhausted immune state occurred in the tumor stroma in UCB. Further clinical development of immune‐checkpoint inhibitors may be effective for resectable patients with UCB.

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“…A comprehensive review, (67). One example is the IgG1 monoclonal antibody against B7-H3 (MGA271, MacroGenics Inc., USA) that is currently being tested in a phase I trial in patients with different advanced cancers including UC (NCT01391143).…”

Section: Other Immunotherapeutic Strategiesmentioning

confidence: 99%