Platinum Priority – Review – Bladder CancerEditorial by Tom Powles on pp. 280–282 of this issueA Systematic Review of Immunotherapy in Urologic Cancer: Evolving Roles for Targeting of CTLA-4, PD-1/PD-L1, and HLA-G☆
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
References (75)
- et al.
The interaction properties of costimulatory molecules revisited
Immunity
(2002) - et al.
Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study
Ann Oncol
(2013) - et al.
Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial
Lancet Oncol
(2012) - et al.
Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial
Lancet Oncol
(2012) - et al.
Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial
Lancet Oncol
(2014) - et al.
Randomized, dose-ranging phase II trial of nivolumab for metastatic renal cell carcinoma
Ann Oncol
(2014) - et al.
Association of T-cell co-regulatory protein expression with clinical outcomes following radical cystectomy for urothelial carcinoma of the bladder
Eur J Surg Oncol
(2014) - et al.
Inhibition of PD-L1 by MPDL3208a leads to clinical activity in patients with metastatic urothelial bladder cancer
Ann Oncol
(2014) - et al.
Beyond the increasing complexity of the immunomodulatory HLA-G molecule
Blood
(2008) - et al.
The tolerogenic interplay(s) among HLA-G, myeloid APCs, and regulatory cells
Blood
(2011)
HLA-G: from biology to clinical benefits
Trends Immunol
Tumor-specific upregulation of human leukocyte antigen-G expression in bladder transitional cell carcinoma
Hum Immunol
B7 family checkpoint regulators in immune regulation and disease
Trends Immunol
Coinhibitory molecules in hematologic malignancies: targets for therapeutic intervention
Blood
B7-H3 over expression in prostate cancer promotes tumor cell progression
J Urol
Evaluation of B7-H3 expression as a biomarker of biochemical recurrence after salvage radiation therapy for recurrent prostate cancer
Int J Radiat Oncol Biol Phys
CD28 and CTLA-4 coreceptor expression and signal transduction
Immunol Rev
A molecular perspective of CTLA-4 function
Annu Rev Immunol
CD28/B7 system of T cell costimulation
Annu Rev Immunol
CTLA-4 control over Foxp3+ regulatory T cell function
Science
Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade
Cancer Res
Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer
Clin Cancer Res
Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer
J Transl Med
A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer
Clin Cancer Res
Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF
Cancer Res
A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates
Cancer Immunol Immunother
T cell profiling reveals high CD4+CTLA-4+ T cell frequency as dominant predictor for survival after prostate GVAX/ipilimumab treatment
Cancer Immunol Immunother
Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer
Cancer Immunol Immunother
Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis
J Immunother
Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer
J Immunother
Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma
Cancer
Association between the cytotoxic T-lymphocyte antigen 4 +49A/G polymorphism and bladder cancer risk
Tumour Biol
Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial
Clin Cancer Res
Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation
J Exp Med
B7-Dc, a New dendritic cell molecule with potent costimulatory properties for T cells
J Exp Med
Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death
EMBO J
PD-1 and its ligands in tolerance and immunity
Annu Rev Immunol
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