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Platinum Priority – Review – Bladder Cancer
Editorial by Tom Powles on pp. 280–282 of this issue

A Systematic Review of Immunotherapy in Urologic Cancer: Evolving Roles for Targeting of CTLA-4, PD-1/PD-L1, and HLA-G eulogo1

By: Edgardo D. Carosella a b , Guillaume Ploussard c , Joel LeMaoult a b and Francois Desgrandchamps a b c

European Urology, Volume 68 Issue 2, August 2015, Pages 267-279

Published online: 01 August 2015

Keywords: Cancer immunotherapy, Monoclonal antibodies, Checkpoint, CTLA-4, PD-1, HLA-G

Abstract Full Text Full Text PDF (1,0 MB) Patient Summary

Abstract

Context

Overexpression of immune checkpoint molecules affects tumor-specific T-cell immunity in the cancer microenvironment, and can reshape tumor progression and metastasis. Antibodies targeting checkpoints could restore antitumor immunity by blocking the inhibitory receptor-ligand interaction.

Objective

To analyze data and current trends in immune checkpoint targeting therapy for urologic cancers.

Evidence acquisition

Systematic literature search for clinical trials in the PubMed and Cochrane databases up to August 2014 according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Endpoints included oncologic results, tumor response rates, safety, and tolerability.

Evidence synthesis

Anti-CTLA-4 monotherapy has demonstrated biochemical responses in prostate cancer. One phase 3 trial assessing ipilimumab efficacy in castration-resistant disease was negative overall. Nevertheless, ipilimumab may significantly improve overall survival compared with placebo in subgroups of patients with favorable prognostic features. In renal cancer, phase 1 trials showed interesting stabilization or long-lasting objective response rates approaching 50% using anti-PD-1/PD-L1 drugs in heavily pretreated metastatic patients. In bladder cancer, one phase 2 trial indicated a good safety profile for ipilimumab as a neoadjuvant drug before radical cystectomy. Overall, immune-related effects such as colitis and dermatitis were common and well tolerated.

Conclusions

Our systematic review shows that antibodies blocking immune checkpoints offer interesting and long-lasting response rates in heavily pretreated patients with advanced urologic cancers. More promising results are currently provided by anti-CTLA-4 antibodies in prostate cancer and by PD-1/PD-L1 inhibitors in renal cancer. These should encourage new clinical trials of immune therapy combinations and immunotherapy monotherapy combined with conventional anticancer drugs. In bladder cancer, the use of targeted immunotherapy still remains underevaluated; however, preliminary results reported at recent conferences seem encouraging.

Patient summary

Data from studies support the activity and safety of immune checkpoint inhibitors in urologic cancers, alone or in combination with conventional cancer therapies. Encouraging data in other oncologic fields could translate into interesting responses in urological cancers.

Take Home Message

Our systematic review shows that antibodies that block immune checkpoints offer interesting and long-lasting response rates in heavily pretreated patients with advanced urologic cancers. Promising results have been observed for anti-CTLA-4 antibodies in prostate cancer and for PD-1/PD-L1 inhibitors in renal cancer.

Keywords: Cancer immunotherapy, Monoclonal antibodies, Checkpoint, CTLA-4, PD-1, HLA-G.

1. Introduction

To survive and proliferate, tumors adopt active immune escape strategies that protect them from antitumor immunity. To restore antitumor immune efficiency, immune escape mechanisms must be bypassed, overridden, or cancelled. Current cancer immunotherapy strategies mostly aim at restoring T-cell–mediated antitumor immunity. T-cell–mediated immunity includes multiple sequential steps: clonal selection of antigen-specific cells, activation, proliferation, trafficking, and execution of direct effector function. Each step is regulated by a balance between stimulatory and inhibitory signals. Immune checkpoints are the inhibitory pathways that physiologically counterbalance the co-stimulatory pathways to fine-tune the immune responses. In other words, immune checkpoints are normal immune signals capable of stopping an immune response. They involve inhibitory receptors and their ligands ( Fig. 1 and Fig. 2 ): one is expressed by a putative target cell and the other is expressed by effector cells, in particular T cells. Under normal physiological conditions, immune checkpoint pathways are crucial for self-tolerance maintenance, modulation of the duration and strength of normal physiological immune responses, and minimization of collateral damage to healthy tissues. Thus, overexpression of immune checkpoint molecules by tumor cells profoundly affects tumor-specific T-cell immunity in the cancer microenvironment. This effectively marks tumor cells as not for elimination, and can therefore reshape tumor progression and metastasis. Since most tumor immune escape mechanisms that use immune checkpoints block effector cell functions, antitumor immunity may be restored by antibodies that block the inhibitory receptor-ligand interaction and thus inactivate the immune checkpoints.

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Fig. 1 Upregulation of immune checkpoint receptors on T cell activation. With the exception of ILT2, most immune checkpoint receptors are absent from the resting T-cell surface. T cell activation is initiated by combined signals from TCR:MHC and BD28:B7 engagement. This leads to proliferation, upregulation of proinflammatory cytokine expression, acquisition of effector cell function, which is cytotoxicity in the case of CD8+ cells, and provision of help for CD4+ T cells. Activated T cells are effector T cells. They express immune checkpoint receptors, and have therefore become sensitive to inhibition by ligands expressed by tumor cells or within the microenvironment. APC = antigen-presenting cell; IFNG = interferon-gamma.

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Fig. 2 Schematic representation of possible engagement of checkpoint proteins leading to T cell inhibition. On engagement of immune checkpoint protein receptors (expressed by activated T cells) by immune checkpoint ligands (expressed by APC or tumor cells), the activated T-cell functions (proliferation, IFNG secretion, and cytotoxic function shown here) are inhibited. Furthermore, immune checkpoint signaling may induce T cell anergy and the differentiation of regulatory T cells whose functions contribute to further inhibition of antitumor immunity. APC = antigen-presenting cell; IFNG = interferon-gamma.

On the basis of these immunology data, monoclonal antibodies capable of disrupting the ligand-receptor association for immune checkpoints and/or its functional consequences were developed. In animal models, such antibodies were successful at restoring antitumor immunity when tumor escape depended on the particular immune checkpoint considered. Thus, immunotherapeutic clinical trials were initiated, some of which are currently ongoing. To date, antibodies blocking immune checkpoints have exhibited oncologic efficacy, including prolongation of overall survival (OS), in various malignancies, mainly breast cancer and melanomas. Here we review immune checkpoints related to urologic cancers with a focus on CTLA-4/B7, PD-1/PD-L1, and HLA-G/ILT-2/4 because of their specific relevance to immunotherapy and clinical trials to modulate them have been conducted.

2. Evidence acquisition

A systematic literature search in the PubMed and Cochrane databases was performed to identify clinical and randomized controlled trials (RCTs) published up to August 2014. Various algorithms including the following terms were used: bladder cancer, prostate cancer, renal cancer, immunotherapy, CTLA-4, PD-1, PD-L1, MHC-II, B7-H1, B7-H3, B7-H4, TIM3, HLA-G, and each molecule under development ( Table 1 ). Given that targeted immunotherapy is a fast-moving field, we also searched abstracts from the major oncology conferences during 2012–2014. Inclusion criteria used were published full articles, clinical trials, retrospective series, meta-analyses, and English language. Our systematic review focused on published clinical trials according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Primary outcomes included oncologic results and tumor response rates. Secondary outcomes included safety and tolerability. The flow diagram for article selection is shown in Figure 3 . Each identified article was analyzed and classified.

Table 1 Immune checkpoint targets in cancer immunotherapy

Target Function Antibody or Ig fusion protein Description Indication Clinical development Company
CTL-4 Inhibitory receptor Ipilimumab Fully human IgG1 mAb Unresectable metastatic melanoma FDA approval Bristol Myers Squibb
Urothelial carcinoma Phase 2
Metastatic CRPC

RCC
Phase 2

Phase 1b and 2
Tremelimumab Fully human IgG2 mAb Advanced melanoma

PSA-recurrent prostate cancer and RCC
Phase 3

Phase 1
Pfizer
PD-1 Inhibitory receptor Nivolumab (BMS-936558; ONO-4538; MDX-1106) Fully human IgG4 mAb Metastatic melanoma

NSCLC

RCC

CRPC
Approval for treatment

Phase 3

Phase 3

Phase 1
Bristol-Myers Squibb
Lambrolizumab (MK-3475) Humanized IgG4 mAb NSCLC, RCC, melanoma

Triple-negative breast cancer, metastatic bladder cancer, and head and neck cancer
Phase 3

Phase 1
Merck
Pidilizumab (CT-011) Humanized IgG1 mAb DLBCL, colon cancer, multiple myeloma, acute leukemia, pancreatic and bladder cancers Phase 2 CureTech
AMP-224 PD-L2 (B7-DC) human IgG1 fusion protein Solid tumors, cutaneous T-cell lymphoma Phase 1 GlaxoSmithKline/Amplimmune
PD-L1 Ligand for PD-1 BMS-936559 (MDX-1105) Fully human IgG4 mAb NSCLC, melanoma, RCC, pancreatic, gastric, and breast cancers Phase 1 Bristol Myers Squibb
RG7446/MPDL3280 Fully human IgG1 mAb (engineered Fc domain optimized) Bladder cancer

NSCLC
Phase 1

Phase 3
Roche/Genentech
MEDI4736 (B7-H1 a ) Fully human IgG1 mAb NSCLC Phase 3 Medimmune
MHCII b Enhancing TReg cell ImmuFact IMP321 Soluble LAG-3 Ig fusion protein Breast cancer

Metastatic RCC
Phase 3

Phase 1/2a
Immutep
B7-H3 (CD276) Inhibitory ligand MGA271 Fully human IgG1 mAb (engineered Fc domain optimized) Solid tumors in multiple cancers Phase 1 MacroGenics
B7-H4 Inhibitory ligand Fully human IgG mAb Preclinical development
TIM3 Inhibitory receptor Mouse mAb Preclinical development
HLA-G Inhibitory ligand Mouse mAb Preclinical development

a B7 homology 1, PD-L1.

b LAG-3 (CD223) ligand of MHCII antigen-presenting cell activation.

CRPC = castration-resistant prostate cancer; DLBCL = diffuse large B-cell lymphoma; FDA = US Food and Drug Administration; Ig = immunoglobulin; LAG-3 = lymphocyte activation gene 3; mAb = monoclonal antibody; NSCLC = non-small-cell lung carcinoma; PSA = prostate-specific antigen; RCC = renal cell carcinoma; TIM3 = T-cell membrane protein 3.

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Fig. 3 Flow chart for article selection. Clinical trials reporting oncologic results, tumor response rates, safety, and tolerability for use of antibodies blocking immune checkpoints in prostate, kidney, and bladder cancer.

3. Evidence synthesis

3.1. Antitumor activity

3.1.1. CTLA-4

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4; also known as CD152) is expressed exclusively on T cells. CTLA-4 primarily regulates the amplitude of early-stage T-cell activation. One of its mechanisms of action involves antagonism of B7-CD28–mediated co-stimulatory signals, which occurs because CTLA-4 has a much higher affinity for B7 than CD28 does: binding of CTLA-4 to CD80/86 is 500–2500 times greater than that of CD28. Signaling through CD28 promotes mRNA expression of the cytokine IL-2 and entry into the cell cycle, T-cell survival, T-helper-cell differentiation, and immunoglobulin isotype switching. Thus, signaling through CTLA-4 inhibits IL-2 mRNA production and inhibits cell cycle progression. This mechanism only depends on the extracellular domain of CTLA-4 [1] and [2]. A second mechanism by which CTLA-4 can inactivate T cells involves delivery of a negative signal. This mechanism requires the cytoplasmic tail of CTLA-4 and occurs at low levels of surface expression [3] . In most cases, the inhibitory actions of CTLA-4 occur via its association with the tyrosine phosphatases SHP1, SHP2, and PP2A.

CTLA-4 is expressed by activated CD8+ effector T cells. However, its major physiological role seems to be through distinct effects on CD4+ T cells, including downregulation of helper T (TH) cell activity and enhancement of regulatory T cell (TReg) immunosuppressive activity [4] and [5]. CTLA-4 blockade results in broad enhancement of the immune responses that depend on TH cells.

3.1.1.1. Prostate cancer

Preclinical studies have supported the potential role of an anti–CTLA-4 antibody (ipilimumab) as an antitumor agent in prostate cancer [6], [7], and [8]. However, only six phase 1/2 trials and one phase 3 trial have been published to date. Outcome data are listed in Table 2 .

Table 2 Outcome data from clinical trials of immune checkpoint inhibitors in urologic cancers

Clinical trial Phase Treatment Patients Population Endpoints Follow-up (mo) OS

(mo)
Factors favoring drug

(subgroup analysis)
Conclusion
Prostate cancer
CTLA-4
Ipilimumab [16] 3 10 mg/kg vs placebo (1:1)



Bone-directed RT 8 Gy before inclusion
799 mCRPC

Post-CT
(i) OS



(ii) PFS
9.6 11.2 vs 10.0 Race (white)

ECOG score 0

ALP <1.5 times the upper limit of normal (ULN)

Gleason score>7

Normal LDH level

No visceral metastases b

Hemoglobin >110 g/L

Not North America region

Low pain score
(i) NS (p = 0.053)

OS 0–5 mo: HR 1.46 (1.1–1.9)

OS 5–12 mo: HR 0.65 (0.5–0.8)

OS >12 mo: HR 0.60 (0.4–0.9)



(ii) S (p<0.0001)
Ipilimumab [9] 1/2 10 mg/kg

±RT (n = 34)
50 c mCRPC Safety

PSA response

RECIST
15.7 17.4 N/A PSA decline >50%: 16%

RECIST criteria:

Complete (3.6%)

Partial (7.1%)

Stable (21.4%)
Ipilimumab [10] 1 3 mg/kg 14 mCRPC (i) Safety

(ii) PSA response
N/A N/A N/A PSA decline >50%: 14.3%

Ipilimumab + GM-CSF [11] 1 Ipilimumab 3 mg/kg

+ GM-CSF
6 d mCRPC (i) Safety

(ii) PSA response (ii) RECIST
N/A N/A N/A PSA decline >50%: 50%

RECIST criteria:

Complete (0)

Partial (16.7%)
Ipilimumab + vaccines [12] and [13] 1 1, 3, 5, 10 mg/kg

+ PROSTVAC
30 mCRPC (i) Safety

(ii) PSA response
N/A 34.4 No previous CT

Immune biomarkers (PD1+CD4+, CTLA-4/TReg)
PSA decline>50%: 50%

Ipilimumab + vaccines [14] and [15] 1 3 mg/kg

+ GVAX
16 e mCRPC (i) Safety

(ii) PSA response
N/A 29.2 PSMA antibody response

Immune biomarkers

(T-cell regulation, low TReg levels, CD4+/CTLA-4+)
PSA decline >50%: 25%

(including e )
Tremelimumab [17] 1 3–6 mg/kg

+ bicalutamide 150 mg 6 mo
11 Rising PSA after local treatment (i) Safety

(ii) PSA kinetics
N/A N/A N/A No significant increase in PSA doubling time
PD-1
Nivolumab [29] and [35] 1 10 mg/kg 17 CRPC (i) Safety

(ii) RECIST
N/A N/A N/A No objective response
Bladder cancer
CTLA-4
Ipilimumab [22] 2 3–10 mg/kg 12 Neoadjuvant

precystectomy
(i) Safety

(ii) Immune monitoring
7-33 N/A N/A Correlation between OS and increase in CD4+ICOS+ T cells
Kidney cancer
CTLA-4
Ipilimumab [18] 2 3 then 1 mg/kg

3 then 3 mg/kg
61 mRCC (i) Safety

(ii) RECIST
N/A N/A Severity of immune-related adverse effects

No previous IL-2 therapy
Response rate 12.5% a
Tremelimumab [20] 1 6, 10, 15 mg/kg

+ sunitinib
28 mRCC (i) Safety

(ii) RECIST
Partial response 42%
PD-L1
BMS-936559 [35] 1 0.3, 1, 3, 10 mg/kg 17 mRCC (i) Safety

(ii) RECIST
NA NA NA Objective response 11.8%

Stabilization 41%
PD-1
Nivolumab [29] and [36] 1 10 mg/kg 34 mRCC (i) Safety

(ii) RECIST
NA NA PD-L1-positive tumors

(response rate 36% vs 0%; p = 0.0006)
Objective response: 27%

Stabilization: 27%
MHC II
IMP321 [69] 1 0.05–30 mg 21 mRCC (i) Pharmacokinetics

(ii) Safety, RECIST
NA NA Dose >6 mg Stabilization 34.5%

No objective response

a In the 40 patients receiving 3 mg/kg at each dose.

b Significant in multivariate analysis.

c Prior dose-escalation phase involving 21 patients (drug doses 3 and 5 mg/kg).

d Prior dose-escalation phase involving 18 patients (drug doses 0.5 and 1.5 mg/kg).

e Prior dose-escalation phase involving 12 patients (drug doses 0.3, 1. and 3 mg/kg).

ALP = alkaline phosphatase; CT = chemotherapy; ECOG = Eastern Cooperative Oncology Group; GM-CSF = granulocyte/macrophage colony-stimulating factor; HR = hazard ratio; LDH = lactate dehydrogenase; mCRPC = metastatic castration-resistant prostate cancer; mRCC = metastatic renal cell carcinoma; NA = not applicable (or not reported); NS = not significant; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; RT = radiotherapy; S = significant.

In phase 1/2 trials, anti–CTLA-4 blockade monotherapy led to biochemical responses (prostate-specific antigen decline >50%) in approximately 15% of cases [9] and [10]. A combination of ipilimumab with granulocyte-macrophage colony-stimulating factor or vaccines seemed to improve the biochemical tumor response rate by up to 25–50% [11], [12], [13], [14], and [15]. Use of a vaccine that enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Most patients included in these trials had very advanced castration-resistant prostate cancer (CRPC) that was refractory to various therapies including chemotherapy. Moreover, when obtained, objective responses tended to have a sustainable effect over time.

One phase 3 RCT has been recently reported ( Table 2 ) [16] . This trial assessed the efficacy of ipilimumab at the dose of 10 mg/kg every 3 wk for up to four cycles in comparison with placebo in metastatic CRPC (mCRPC). After a mid-term follow-up of less than 12 mo, this study was negative overall (median survival 11.2 vs 10.0 mo; p = 0.053). However, subgroup analyses suggested that ipilimumab might provide an OS benefit for patients with favorable prognostic features and who do not have a heavy metastatic burden. For the subgroup of patients with favorable prognostic features, ipilimumab significantly improved OS compared with placebo (hazard ration [HR] 0.64; p = 0.0038). Treatment with ipilimumab also significantly improved progression-free survival compared with placebo in the overall cohort (4.0 vs 3.1 mo; p < 0.001).

Another key point was the delayed benefit reported in patients receiving ipilimumab. Whereas short-term OS did not differ between the ipilimumab and placebo arms, survival curves began to diverge after 5 mo. The 2-yr OS rate was 26.2% in the ipilimumab group and only 15.0% in the placebo group. Continuing survival follow-up is warranted to draw strong conclusions and address whether blocking of this immune checkpoint provides a survival advantage in mCRPC patients. Studies in advanced melanoma patients have suggested that the length of follow-up is fundamental when assessing the sustainability of survival benefit of ipilimumab treatment. In chemotherapy-naïve prostate cancer and neoadjuvant settings, numerous clinical studies assessing ipilimumab at an early stage are also under way ( NCT01194271 , NCT01057810 ).

Another anti-CTLA4 antibody, tremelimumab, was evaluated in a phase 1 trial [17] . Only 11 patients treated for biochemical recurrence after local therapy were included. Although the safety profile was good, no oncologic data are yet available.

3.1.1.2. Kidney cancer

Immune-based therapy using IL-2 has an objective response rate of 20% in renal cancer. Despite this relatively low rate, a minority of patients have been cured by this therapy and the majority of tumor regression was long-lasting, leading to continued interest in immunotherapy for renal cancer management.

To date, three clinical trials have tested ipilimumab or tremelimumab as antitumor agents in patients with metastatic renal cancer [18], [19], and [20].

The first phase 1 trial of ipilimumab only reported the incidence of autoimmune hypophisitis in a mixed cohort of patients treated for melanoma (n = 113) or renal cancer (n = 50) [19] . A more mature phase 2 trial investigated the safety of ipilimumab and the response rate in 61 patients with metastatic renal cell carcinoma (RCC) [18] . The objective partial response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) was 12.5%. No complete response was noted. The duration of the response ranged from 7 to 21 mo. The absence of a previous IL-2 regimen and the severity of immune-related toxicity were associated with tumor regression and its sustainability.

A phase 1 dose-escalation trial investigated the combination of sunitinib and tremelimumab in 28 patients with metastatic RCC [20] . Three doses of tremelimumab (6, 10, and 15 mg/kg) were investigated in combination with sunitinib. Twenty-one patients were evaluable for tumor response, of whom nine (43%) showed objective partial responses. A median response duration was not achieved. Nevertheless, from comparisons with data available from phase 3 trials of sunitinib alone, the authors concluded that the objective response rate did not differ obviously with the addition of tremelimumab.

3.1.1.3. Bladder cancer

Few preclinical studies have investigated the role of CTLA-4 in bladder cancer carcinogenesis or aggressiveness. A recent report highlighted a significant association between CTLA-4 polymorphism and bladder cancer risk in a case-control study [21] .

Given the ongoing trials assessing ipilimumab in other urologic malignancies, one phase 2 trial investigated the safety and efficacy of ipilimumab as a neoadjuvant drug before radical cystectomy in muscle-invasive bladder cancers ( Table 2 ) [22] . Twelve patients receiving ipilimumab at a dose of 3–10 mg/kg for two cycles were included. In this presurgical setting, the safety profile was acceptable and measurable immunologic effects were noted. Further trials are warranted to assess the oncologic and pathologic impact of such effects.

3.1.2. PD-1/PD-L1

Programmed death 1 (PD-1) is more broadly expressed than CTLA-4: it is induced on other activated non–T-lymphocyte subsets, including B cells and natural killer (NK) cells, in which it limits lytic activity. Therefore, PD-1 blockade, which enhances the activity of effector T cells, should also enhance NK cell activity in tumors and tissues, and antibody production. PD-1 ligand 1 (PD-L1; also known as B7-H1 or CD274) and PD-1 ligand 2 (PD-L2; also known as B7-DC or CD273) are the two ligands of PD-1 [23] and [24].

In contrast to CTLA-4, which regulates T-cell activation, the major role of PD-1 [25] is to limit the activity of T cells in peripheral tissues at the time of an inflammatory response to infection, and to limit autoimmunity [26] . This translates into a major immune resistance mechanism within the tumor microenvironment [27] . PD-1 expression is induced when T cells are activated ( Fig. 1 ) [25] . Engagement of PD-1 by a ligand during antigen recognition induces cross-linkage of the antigen-receptor complex with PD-1. This results in phosphorylation of the tyrosine residue in the immunoreceptor tyrosine-based switch motif of PD-1 and recruits the tyrosine phosphatase SHP-2, which dephosphorylates and inactivates proximal effector molecules such as Syk in B cells and Zap70 in T cells. The immediate outcome of stimulation via PD-1 is inhibition of cell growth and cytokine secretion [28] .

PD-1 is highly expressed on TReg cells, where it may enhance their proliferation in the presence of a ligand. Thus, because many tumors are infiltrated with TReg cells, blockade of the PD-1 pathway may also enhance antitumor immune responses by diminishing the number and/or suppressive activity of intratumoral TReg cells.

3.1.2.1. Prostate cancer

A recent multicenter phase 1 trial assessed the efficacy and safety profile of nivolumab, a fully human anti–PD-1 antibody, in a cohort of 296 patients with advanced cancer ( Table 2 ) [29] . Only 17 CRPC patients were enrolled and treated with nivolumab. Whereas antitumor activity was seen in melanoma, lung cancer, and RCC patients, no objective response was reported for CRPC. Immunostaining for PD-L1 expression has been suggested to explain these discrepancies in antitumor activity. Prostate cancer shows low levels of PD-L1 expression, although T cells surrounding the prostate are positive for PD-1 [30] . All CRPC cases stained for PD-L1 expression in the study by Topalian et al. [29] were negative, in accordance with previous immunohistochemistry cohorts [31] . Phase 1b/2 trials are investigating the use of these PD-1/PD-L1 agents in prostate cancer ( NCT01420965 , NCT00730639 ).

3.1.2.2. Kidney cancer

PD-1 expression in RCC, blood, tumors, and tumor-infiltrating lymphocytes has been independently associated with an increased risk of overall and cancer-specific mortality [32], [33], and [34].

In kidney cancer, drugs targeting the PD-1/PD-L1 pathway have been tested in the metastatic setting [29], [35], and [36].

Tumor response to an anti–PD-L1 antibody was assessed as a secondary endpoint in a phase 1 trial in 17 patients with metastatic RCC [36] . A total of 207 patients with advanced cancers (melanoma, lung, colorectal, ovarian, pancreatic) were included to test anti–PD-L1 drug safety. Before inclusion, 94%, 82%, and 41% of RCC patients had been treated using nephrectomy, antiangiogenic therapy, and immunotherapy, respectively. An objective response according to RECIST criteria was observed in two patients (12%) with a durable response lasting 4 and 17 mo. Stable disease lasting at least 24 wk was observed in seven additional patients (41%). No survival data were available.

In a phase 1 trial assessing nivolumab (anti–PD-1), an objective response rate of 27% was estimated in 34 RCC patients [29] and [35]. At a dose of 10 mg/kg, the response duration ranged from 8 to 22 mo. In line with the anti–PD-L1 antibody trial, patients were heavily pretreated. Interestingly, objective responses were observed in various metastasis sites. Disease stabilization was also noted in 27% of patients, suggesting that more than half of tumors responded to nivolumab with prolonged disease control. The 6-mo progression-free survival rate was 56%.

The superiority of one agent over the other should be evaluated in a dedicated direct comparison trial.

It has been noted in other malignancies that anti-PD-1/PD-L1 therapy may induce transient worsening of disease progression and that tumor responses may be delayed. Nevertheless, the objective response rate and the prolonged disease stabilization, even after discontinuation of immune therapy, encouraged further clinical trials. Several phase 1/2 trials are studying the use of anti–PD-1 and anti–PD-L1 agents in renal cell cancers, and updated analyses from already published trials confirmed durable clinical activity and interesting response rates ( NCT01472081 , NCT01668784 , NCT01354431 , NCT01441765 , NCT01984242 ). Preliminary results from NCT01375842 assessing the PD-L1 antibody MPDL3280a have been presented, revealing 6-mo progression-free survival of 50% [37] . Results from a randomized dose-ranging trial of nivolumab for metastatic renal cancer were presented at the 2014 European Society for Medical Oncology (ESMO) conference [38] . Overall, more than half of patients had objective responses lasting for >1 yr. Combinations of nivolimab with pazopanib or sunitinb are also being tested and show comparable 50% objective response rates [39] . Further clinical investigations should also focus on theranostic factors. Preliminary data demonstrated that PD-L1 expression might be an interesting predictive biomarker for response to PD-1 and PD-L1 inhibitors [40] and [41]. In the nivolumab trial, an objective response rate of 36% was observed for PD-L1-positive tumors, in contrast to none for PD-L1-negative tumors.

3.1.2.3. Bladder cancer

PD-L1 immunohistochemistry in urothelial cancer has suggested that PD-L1 expression is associated with tumor aggressiveness [42] and [43]. PD-1 and PD-L1 were altered in a large proportion of urothelial cancers and, more importantly, PD-L1 expression predicted overall mortality after cystectomy for patients with organ-confined tumors, suggesting that PD-L1 manipulation may be a beneficial immunotherapy target in muscle-invasive bladder cancers [44] and [45].

At least one phase 1 trial is under way to assess the safety of a fully human anti–PD-L1 antibody, as well as two phase 1/2 trials of anti–PD-1 drugs (lambrolizumab, pidilizumab). Preliminary results from the phase 1b KEYNOTE-012 ( NCT01848834 ) study were presented at the last ESMO conference [46] . Thirty-three heavily pretreated (at least two prior therapies) patients with advanced urothelial cancer were enrolled. A response rate of 24% was reported. Inhibition of PD-L1 also showed encouraging results, with a 43% response rate for PD-L1 positivity on tumor biopsy [47] . In a recent phase 1 expansion study with an adaptive design that allowed for biomarker-positive enriched cohorts, tumors expressing PD-L1–positive tumor-infiltrating immune cells had particularly high response rates [48] .

3.1.3. HLA-G

HLA-G is a nonclassical HLA class I molecule whose primary function is to protect the fetus from destruction by the mother's immune system, playing a role in maternal-fetal tolerance [49], [50], [51], and [52]. Thus, HLA-G is one of the few proteins whose physiological immune checkpoint function is exerted primarily towards foreign tissues. Under normal physiological conditions, HLA-G is hardly expressed by adult tissues. By contrast, most tumors neoexpress HLA-G at different stages of their evolution, either on their cell surface or released as soluble forms. In vitro and in vivo studies of the function of HLA-G revealed a broad immunoregulating function that affects both innate and adaptive immune responses. Through its receptors LILRB1, LILRB2 (also known as ILT2/CD85j and ILT4/CD85d), and KIR2DL4, which are differentially expressed by immune cells, HLA-G inhibits the cytolytic function of uterine and peripheral blood NK cells, the antigen-specific cytolytic function of cytotoxic T lymphocytes (CTLs) and γ/δT cells, the alloproliferative response of CD4+ T cells, the proliferation of T cells and peripheral blood NK cells, and the maturation and function of dendritic cells (DCs). HLA-G also induces TReg cells and myeloid suppressive cells. Thus, HLA-G is capable of inhibiting all actors in antitumor responses and, in contrast to both CTLA-4 and PD-1, of blocking all stages of such an antitumor response, from APC activation and effector priming, to the function of fully activated CTLs or NK cells.

In cancer, HLA-G is expressed on tumor cells and tumor-infiltrating cells. HLA-G expression is associated with higher tumor grade and worse prognosis [52] . Animal models have demonstrated that anti–HLA-G blocking antibodies restore antitumor immunity against HLA-G–expressing tumor cells in vivo. Furthermore, HLA-G expression was associated with tumor metastasis and poor survival in a humanized mouse model of ovarian cancer [53] .

HLA-G plays a key role in the induction of immune tolerance and constitutes a novel immune escape mechanism of tumor cells. Tissue HLA-G and soluble HLA-G were upregulated in RCC [54] and [55]. However, the therapeutic role of HLA-G peptide-based immunotherapy requires further investigation. HLA-G is also expressed in bladder cancer [56] and [57], and therapeutic anti–HLA-G antibodies are currently in preclinical development for non–muscle-invasive bladder cancer.

3.1.4. Other immune checkpoint molecules

The molecules described above are those that have been studied the most and, in the case of CTLA-4 and PD-1, for which clinical developments are the most advanced. Nevertheless, other immune checkpoint proteins have been identified in basic studies, some of which are under clinical evaluation. We briefly describe B7-H3, B7-H4, LAG3, and TIM3.

B7-H3 protein (also known as CD276 [58] ) is physiologically expressed by activated monocytes, T cells, B cells, and NK cells. The receptors for B7-H3 have not been identified and it has been reported that B7-H3 has both stimulatory and inhibitory functions. Thus, B7-H3 is thought to have several ligands that can trigger several, even antagonist functions. B7-H3 expression has been reported for tumor cell lines and/or patient specimens including prostate cancer. It often correlated with increased tumor size. B7-H3 expression is also associated with decreased numbers of tumor-infiltrating lymphocytes and suppression of antitumor T-cell responses.

B7-H4 [59] is a ligand of the B7 family whose receptor is still unknown. Its engagement decreases T-cell proliferation and IL-2 production, as well as expansion of neutrophil progenitors. Besides its immunoinhibitory function, B7-H4 may also directly promote the growth of cancer cells. B7-H4 overexpression has been identified in multiple solid malignancies, including renal cancer. It has been consistently correlated with increasing tumor burden, neovascularization, and poor patient outcomes [60], [61], and [62].

LAG3 (lymphocyte-activation gene 3, also known as CD223 [63] ) is an inhibitory receptor that binds HLA class II molecules. It may be upregulated on tumor cells, and it is expressed at high levels by tumor-infiltrating antigen-presenting cells and macrophages. LAG3 has a dual function: it inhibits T cell functions, in particular those of CD8+ T cells, and enhances the immunoinhibitory functions of TReg cells. A synergic tumor escape function of PD-1 and LAG3 was recently shown in mice.

TIM3 [64] is a receptor for galectin 9, which is upregulated in various types of cancer. TIM3 inhibits TH1 cell responses and is coexpressed with PD-1 on tumor-specific CD8+ T cells. In animal models, blockade of both PD-1 and TIM3 enhanced antitumor immune responses and tumor rejection to a greater extent than blockade of each individual molecule.

3.1.4.1. Prostate cancer

Molecules targeting other immune checkpoints are underevaluated in prostate cancer. However, preclinical and prognostic studies may lead to the promotion of new clinical trials. A high level of B7-H3 expression in prostate cancer has been correlated with tumor progression, proliferation markers, and poor oncologic outcomes, suggesting it is a promising therapeutic target [65], [66], [67], and [68].

3.1.4.2. Kidney cancer

A recombinant soluble LAG-3 fusion protein, IMP 321, which agonizes MHC class II–driven dendritic cell activation, was safe and stabilized advanced renal cancer in a phase 1 trial [69] . Disease stabilization was observed in a third of patients, and this rate reached 87% when the IMP 321 dose was >6 mg/injection. However, the primary endpoints of this study were evaluations of pharmacokinetics and pharmacodynamics, and further clinical investigation is warranted.

To date, no clinical trial evaluating other drugs targeting immune checkpoints has been published. Several molecules are in development and preclinical data support their potential role in renal cancer therapy.

B7-H3 expression is approximately 15% in RCC but reaches 95% in blood vessels surrounding such tumors [70] and [71]. This vascular expression has been associated with adverse clinicopathologic features and with metastatic status. In particular, tumor vasculature B7-H3 expression was significantly associated with an increased risk of death from renal cancer [72] . Similar findings have been suggested for B7-H4 expression [34] .

3.1.4.3. Bladder cancer

No clinical trial investigating the usefulness of other immune blockades in bladder cancer has been published. A target of interest might be B7-H3, whose expression is largely altered in bladder tumors.

The aim of the ongoing NCT01391143 phase 1 trial is to assess the safety of the inhibitory ligand MGA271 in various malignancies, including prostate, kidney, and bladder cancers.

3.2. Safety

Safety was the primary endpoint in most phase 1/2 trials assessing targeted immune therapy in urologic cancers. Overall, immune therapy was relatively well tolerated. However, drug-related adverse events, including immune-related effects, were frequent. The frequency and severity of drug-related adverse events are listed in Table 3 .

Table 3 Toxicity of checkpoint inhibitors used in urologic cancers

Clinical trial Cancer Patients ECOG

score
Grade 3/4 Discontinuation

rate (%)
Most frequent immune-related adverse effects
CTLA-4
Ipilimumab 10 mg/kg [16] Prostate 400 0: 42%

1: 55%

2: 1%
Grade 3: 59% (vs 41%)

Grade 4: 17% (vs 11%)
35 Diarrhea (39%), pruritus (20%), rash (17%), colitis (7%)
Ipilimumab 10 mg/kg [9] Prostate 50 0: 38%

1: 56%

2: 0%
46% 16 Diarrhea (54%), pruritus (20%), rash (32%), colitis (22%)
Ipilimumab 10 mg/kg [12] Prostate 15 0–1 18% 43.3 Diarrhea/colitis (26.7%), rash (53.3%), pan-hypopituitarism (13.3%)
Ipilimumab 10 mg/kg [22] Urothelial 12 NA 33.3% 8.3 Diarrhea/colitis (58.3%), pruritus (25%), rash (58.3%), uveitis (8.3%)
Ipilimumab 3 mg/kg [11] Prostate 6 0–1 50% N/A G3 diarrhea (16.7%), G3 pan-hypopituitarism (16.7%), G3 temporal arteritis (16.7%)
Ipilimumab 3 mg/kg [10] Prostate 14 0: 71%

1: 28%
Grade 3: 21%

Grade 4: 0
N/A Diarrhea (21.4%), rash (14.3%), pruritus (7.1%)
Ipilimumab 3 mg/kg [14] Prostate 16 0: 94%

1: 6%
Grade 3: 29%

Grade 4: 4%
19 Colitis (19%), hypophysitis (13%), hepatitis (6%)
Ipilimumab 3 mg/kg [18] RCC 61 0: 61%

1: 40%
Grade 3: 27.9%

Grade 4: 3.3%

Grade 5: 1.6%
N/A Colonic perforation (5%), diarrhea/colitis (27.8%), hypopituitarism (3.3%), adrenal insufficiency (1.6%)
Tremelimumab [17] Prostate 11 0: 91%

1: 9%
Grade 3: 27.3%

Grade 4: 0
9.1 Diarrhea (27.3%), pruritus (27.3%), rash (36.4%), colitis (9.1%)
Tremelimumab + sunitinib [20] mRCC 28 0: 64%

1: 36%
61% Colitis
PD-1
Nivolumab 10 mg/kg [29] Prostate

RCC

Other cancers
17

34

245
0-2 14% N/A Diarrhea (9%), rash (8%), pruritus (7%), dysthyroidism (3%)
PD-L1
BMS-936559 [35] RCC

Other cancers
17

190
0-2 9% 11 Diarrhea/colitis (9%), pruritus (6%), rash (7%), dysthyroidism (4%)
MHC II
IMP 321 [69] RCC 21 0-1 0 0 Infusion reaction (10%)

ECOG = Eastern Cooperative Oncology Group; mRCC = metastatic renal cell carcinoma; NA = not applicable.

The toxicity reported for CTLA-4 blockade includes immune-related adverse effects such as colitis, mostly manifested as diarrhea, dermatitis (pruritus, rash), uveitis, and hypophysitis. Arthritis, hepatitis, iritis, and vitiligo were also seen. Manifestations of immune toxicity are generally treated with systemic steroids. Table 3 shows the rate of grade 3/4 events and the most frequent immune-related adverse effects. Rash and diarrhea are frequent, occurring in approximately 30–40% of patients. The overall rate of grade 3/4 toxicity ranged from 20% to >50% among studies. Grade 5 adverse effects have also been noted, with a significant rate of colonic perforation due to severe colitis in renal cancer patients [18] and [20].

It has been suggested that the immune-related adverse effects of anti–CTLA-4 antibodies and their severity are correlated with objective tumor responses [18] and [72].

The type of immune-related adverse events for anti–PD-1/PD-L1 agents was similar to that seen with ipilimumab [73] . Dermatological adverse events, diarrhea, and fatigue occurred in approximately 20%, 20%, and 30% of cases, respectively. Severe colitis was infrequent. Pneumonitis has also been observed after the use anti-PD-1 agents [35] . Although anti–CTLA-4 and anti–PD-1/PD-L1 antibodies have not been directly compared, immune-related effects associated with anti–CTLA-4 drugs were more common and of higher grade. Thus, approximately 10% of patients experienced grade 3/4 adverse effects after using anti–PD-1/PD-L1 antibodies, compared with 20–50% after using CTLA-4 inhibitors. Infusion reactions were more frequently observed with anti–PD-L1 therapy (10%). It has been suggested that the level of PD-L1 expression in tumor tissue is correlated with the severity of toxicity.

Toxicity induced by agents targeted at other immune checkpoints is expected to be quite similar to that reported for anti–CTLA-4 and anti–PD-1/PD-L1 antibodies. However, the lack of published reports for phase 1/2 trials currently precludes strong conclusions for urologic cancer patients.

4. Conclusions

An improved understanding of the molecular mechanisms that govern interactions between a tumor and the host immune response has led to major advances in targeted immunotherapy and cancer treatments. Our systematic review demonstrates that immune checkpoint inhibitors offer interesting and long-lasting response rates in heavily pretreated patients with advanced urologic cancers.

In prostate cancer, a growing body of data supports the oncologic role of anti–CTLA-4 antibodies, alone or in combination with other immune therapies. A recent phase 3 trial assessing ipilimumab in castration-resistant prostate cancer is negative; nevertheless, interesting response rates in cancers with favorable features encourage further investigations and longer follow-up. Despite better tolerability, PD-1/PD-L1 inhibitors have not yet shown satisfactory oncologic outcomes in prostate cancer.

In renal cancer, the most encouraging findings have been observed for PD-1/PD-L1 inhibitors given their safety and antitumor activity. Recent presentations at 2014 oncology conferences highlighted interesting and long-lasting tumor response rates (∼50%). Final publications for these trials are awaited. The superiority of one agent over the other should be evaluated in a dedicated head-to-head comparison trial. In bladder cancer, the use of targeted immunotherapy remains underevaluated and further trials are awaited.

The field of immunotherapy in urologic cancer treatment is evolving. Oncologic efficacy, including prolongation of overall survival, has already been observed for immune checkpoint inhibitors in various malignancies, mainly in breast cancer and melanomas. Several ongoing trials are studying immune therapy combinations and immune monotherapy combined with conventional anticancer drugs ( Table 4 ). An anti–CTLA-4 antibody and vaccine combination has already been tested with interesting outcomes. Preclinical studies also support the synergistic role of CTLA-4 and PD-1 blockade [74] and [75].

Table 4 Ongoing clinical trials

Clinical trial Drug Phase Cancer Estimated

enrollment
Population Primary endpoint Arms Estimated completion

date
CTLA-4
NCT01057810 Ipilimumab 3 Prostate 600 CT-naïve mCRPC OS Versus placebo February 2016
NCT01530984 Ipilimumab 2 Prostate 54 CT-naïve mCRPC PSA decline Versus ipilimumab + GM-CSF December 2018
NCT01688492 Ipilimumab 1/2 Prostate 25 CT-naïve mCRPC PSA decline With abiraterone September 2015
NCT01498978 Ipilimumab 2 Prostate 30 mCRPC PSA decline April 2018
NCT01194271 Ipilimumab 2a Prostate 20 Localized Immune response Neoadjuvant September 2015
NCT01804465 Ipilimumab 2 Prostate 66 CT-naïve mCRPC Immune response With sipuleucel-T December 2016
NCT02231749 Ipilimumab 3 RCC 1070 mRCC OS, PFS With nivolumab versus sunitinib October 2019
NCT01524991 Ipilimumab 2 Bladder 36 M OS With GC June 2016
PD-1
NCT01354431 Nivolumab 2 RCC 150 mRCC RECIST April 2015
NCT01668784 Nivolumab 3 RCC 822 mRCC RECIST Versus everolimus September 2016
NCT01441765 Pidilizumab 2 RCC 44 mRCC RECIST ± dendritic cell vaccine November 2015
NCT01420965 Pidilizumab 2 Prostate 57 mCRPC Immune response With sipuleucel ± cyclophosphamide December 2018
NCT02210117 Nivolumab 2 RCC 45 mCRPC Safety ± sunitinib versus ± ipilimumab January 2019
NCT01928394 Nivolumab 1/2 Bladder 410 M Response rate ± ipilimumab March 2017
PD-L1
NCT01984242 MPDL3280A 2 RCC 150 mRCC RECIST ± sunitinib versus bevacizumab January 2016
NCT02108652 MPDL3280A 2 Bladder 330 M Response rate March 2016
B7-H3
NCT01391143 MGA271 1 Prostate Bladder

RCC
151 M Safety February 2016

CRPC = castration-resistant prostate cancer; RCC = renal cell carcinoma; m = metastatic; GM-CSF = granulocyte/macrophage colony-stimulating factor; OS = overall survival; PSA = prostate-specific antigen; PFS = progression-free survival; CT = chemotherapy; RECIST = Response Evaluation Criteria in Solid Tumors; GC = gemcitabine and cisplatin.

The continual development of new drugs highlights the need to improve the prediction of response to immune therapies and to optimize sequential therapeutic modalities. Identification of activity and marker correlates should be included in newly opened clinical trials to guide treatment decision-making. In this light, the preliminary data suggest that PD-L1 expression in tumor tissue might be a predictive marker of tumor response to anti-PD-1 antibodies and might guide treatment choice.


Author contributions: Edgardo D. Carosella had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Carosella, Ploussard, LeMaoult, Desgrandchamps.

Acquisition of data: Carosella, Ploussard, LeMaoult, Desgrandchamps.

Analysis and interpretation of data: Carosella, Ploussard, LeMaoult, Desgrandchamps.

Drafting of the manuscript: Carosella, Ploussard, LeMaoult, Desgrandchamps.

Critical revision of the manuscript for important intellectual content: Carosella, Desgrandchamps.

Statistical analysis: None.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Carosella.

Other: None.

Financial disclosures: Edgardo D. Carosella certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

Acknowledgments: We thank Dr. Adrien Riviere, Urology Department, APHP, Saint-Louis Hospital, for his help with the data collection for this review.

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Footnotes

a CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France

b University Paris Diderot, Sorbonne Paris Cité, UMR E_5 Institut Universitaire d’Hematologie, Saint-Louis Hospital, Paris, France

c Urology Department, Saint-Louis Hospital, Paris, France

Corresponding author. CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France. Tel. +33 1 57276778; Fax: +33 1 47276780.

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