Elsevier

European Urology

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

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

https://doi.org/10.1016/j.eururo.2015.02.032Get rights and content

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.

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.

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.

Section snippets

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

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

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

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