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

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

Carosella ED ，Ploussard G ，LeMaoult J ，Desgrandchamps F ... -  《-》

Immune Checkpoint Inhibitors for Urologic Cancer: The Tip of the Iceberg?

Powles T 《-》

Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies.

Despite extensive investigation over the past three decades, cancer immunotherapy has produced limited success, with few agents achieving approval by the Food and Drug Administration and even the most effective helping only a minority of patients, primarily with melanoma or renal cancer. In recent years, immune checkpoints that maintain physiologic self-tolerance have been implicated in the down-regulation of anti-tumor immunity. Efforts to restore latent anti-tumor immunity have focused on antibody-based interventions targeting CTL antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T lymphocytes and its principal ligand (PD-L1) on tumor cells. Ipilimumab, an antibody targeting CTLA-4, appears to restore tumor immunity at the priming phase, whereas anti-PD-1/PD-L1 antibodies restore immune function in the tumor microenvironment. Although ipilimumab can produce durable long-term responses in patients with advanced melanoma, it is associated with significant immune-related toxicities. By contrast, antibodies targeting either PD-1 or PD-L1 have produced significant anti-tumor activity with considerably less toxicity. Activity was seen in patients with melanoma and renal cancer, as well as those with non-small-cell lung, bladder and head and neck cancers, tumors not previously felt to be sensitive to immunotherapy. The tolerability of PD-1-pathway blockers and their unique mechanism of action have made them ideal backbones for combination regimen development. Combination approaches involving cytotoxic chemotherapy, anti-angiogenic agents, alternative immune-checkpoint inhibitors, immunostimulatory cytokines and cancer vaccines are currently under clinical investigation. Current efforts focus on registration trials of single agents and combinations in various diseases and disease settings and identifying predictive biomarkers of response.

Philips GK ，Atkins M 《-》

The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma.

Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma. PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic. The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management. This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

Mahoney KM ，Freeman GJ ，McDermott DF 《-》

Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas.

Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell-mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non-small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4+ and CD8+ T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8+ and CD4+ T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8+ and CD4+ T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8+ TIL, compared with other CD8+ TIL. Compared with TIL that did not express these inhibitory receptors, CD8+ and CD4+ TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8+ and CD4+ TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer.

Zhou G ，Sprengers D ，Boor PPC ，Doukas M ，Schutz H ，Mancham S ，Pedroza-Gonzalez A ，Polak WG ，de Jonge J ，Gaspersz M ，Dong H ，Thielemans K ，Pan Q ，IJzermans JNM ，Bruno MJ ，Kwekkeboom J ... -  《-》