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

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.

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