The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma.
ABSTRACT: 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.
Project description:Advanced melanoma presents a significant therapeutic challenge to clinicians. Many therapies for metastatic melanoma are limited by low response rates, severe toxicities, and/or relatively short response duration. Cancer immunotherapies that act as immune-checkpoint inhibitors to block the localized immune suppression mechanisms utilized by tumors are undergoing development and clinical trials. A clinically relevant immune escape mechanism in melanoma is the activation of the programmed cell death-1 (PD-1) receptor on infiltrating T cells. Activating PD-1 triggers an immune checkpoint resulting in inhibition of T cells directed against melanoma antigens and prevents the immune system from combating the melanoma. In Phase I clinical trials, two anti-PD1 therapies, Nivolumab and MK-3475, that block the PD-1 receptor to enable T cell killing have demonstrated objective tumor responses in patients with advanced melanoma. The purpose of this review is to present the available clinical evidence on anti-PD-1 and anti-PD-L1 immunotherapy for the treatment of advanced melanoma. We also discuss limitations associated with anti-PD-1 therapy. The blockade of the PD-1-PD-L1 pathway has shown promising results in clinical trials and has revolutionized melanoma immunotherapy.
Project description:Background:Nivolumab is an anti-PD-1 antibody that restores the antitumour immune function of T cells, blocking the binding of PD-1 with its ligand PD-L1. PD-1 is expressed on T cells and interacts with PD-L1 on tumour cells. The PD-1-PD-L1 link inhibits T cell activation. In metastatic melanoma, PD-1-PD-L1 binding plays a critical role, and the advent of the immune checkpoint inhibitor nivolumab has delivered new and effective treatment options with proven clinical benefit. In the present study, we evaluated the efficacy of nivolumab in elderly patients with metastatic melanoma. Methods:The study enrolled 55 elderly patients (75 years of age and older) with a diagnosis of metastatic melanoma. Primary endpoints of the study were progression-free survival (pfs) and the objective response rate; secondary endpoints were overall survival, reduction in serum lactate dehydrogenase (ldh) from before to after treatment, and tolerability. Results:Nivolumab was well tolerated and resulted in good disease control, with a manageable toxicity profile and significant clinical benefit. The duration of pfs was 5.1 months (95% confidence interval: 3.5 months to 6.8 months). A significant correlation was observed between reduction in serum ldh and pfs: 0.60 (95% confidence interval: 0.28 to 0.86; p = 0.002). Conclusions:Nivolumab is an immunotherapy treatment that has proved to be an effective and well-tolerated therapeutic option in elderly patients with metastatic melanoma.
Project description:Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab?+?nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.
Project description:Programmed cell death receptor-1 (PD-1) and programmed cell death-1 ligand-1 (PD-L1) represent promising novel targets in immunotherapy. PD-1 is an inhibitory receptor involved in T-cell regulation that is expressed by activated T cells. Nivolumab and pembrolizumab are anti-PD-1 antibodies that have shown antitumor activity and acceptable tolerability in patients with metastatic melanoma in preclinical development and Phase I/II clinical trials. Several ongoing Phase III studies are further investigating the efficacy and safety of anti-PD-1 therapy in melanoma. Initial data on the combination of anti-PD-1 and anti-cytotoxic T-lymphocyte-associated antigen 4 blockade with nivolumab and ipilimumab also appear promising. Monoclonal antibodies to blockade PD-L1 may also be an effective immunotherapy strategy in melanoma and several anti-PD-L1 antibodies are in development.
Project description:Immunotherapy is among the most rapidly evolving treatment strategies in oncology. The therapeutic potential of immune-checkpoint inhibitors is exemplified by the recent hail of Food and Drug Administration (FDA) approvals for their use in various malignancies. Continued efforts to enhance outcomes with immunotherapy agents have led to the formulation of advanced treatment strategies. Recent evidence from pre-clinical studies evaluating immune-checkpoint inhibitors in various cancer cell-lines has suggested that combinatorial approaches may have superior survival outcomes compared to single-agent immunotherapy regimens. Preliminary trials assessing combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 immune-checkpoint inhibitors have documented considerable advantages in survival indices over single-agent immunotherapy. The therapeutic potential of combinatorial approaches is highlighted by the recent FDA approval of nivolumab plus ipilimumab for patients with advanced melanoma. Presently, dual-immune checkpoint inhibition with anti-programmed death receptor-1/programmed cell death receptor- ligand-1 (anti-PD-1/PD-L1) plus anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) monoclonal antibodies (MoAbs) is being evaluated for a wide range of tumor histologies. Furthermore, several ongoing clinical trials are investigating combination checkpoint inhibition in association with traditional treatment modalities such as chemotherapy, surgery, and radiation. In this review, we summarize the current landscape of combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 MoAbs for patients with melanoma and non-small cell lung cancer (NSCLC). We present a synopsis of the prospects for expanding the indications of dual immune-checkpoint inhibition therapy to a more diverse set of tumor histologies.
Project description:Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients.Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4?weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves.Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P?=? 0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P?=? 0.013). Early changes in serum IL-8 levels (2-4?weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P?=? 0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P?=? 0.001) and NSCLC (P?=? 0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression.Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.
Project description:Similar to melanoma, renal cell carcinoma (RCC) has been historically considered as an immunogenic tumor, with interleukin 2 (IL-2) and interferon alpha (IFN-?) being the first approved treatments in the 1990s. However, these therapies were effective in only 10-20% of cases and were not well tolerated. Recently, new insights on the interaction between the immune system and tumor have identified the programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) pathway to be a key player in evading host immune responses. The strategy of immune checkpoint blockade is to reduce inhibitory signaling and restore the patient's natural tumor-specific T-cell-mediated immune responses. Nivolumab is the first PD-1 inhibitor to have gained approval for the treatment of patients with metastatic melanoma, squamous and nonsquamous non-small cell lung cancer (NSCLC), Hodgkin disease and recently RCC. In this review, we discuss results from studies of nivolumab in RCC, clinical experience with this agent, and its future development.
Project description:Immunotherapy has emerged as an exciting strategy for cancer treatment. Therapeutic blockade of immune checkpoint regulators favors the ability of T cell responses to increase anti-tumor immunity. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) are two T cell-inhibitory receptors with independent mechanisms of action. Immune checkpoint inhibitors targeting either CTLA-4, PD-1 or its ligand PD-L1 are currently yielding promising results in terms of efficacy in several clinical studies with melanoma patients and are being developed and tested as immunotherapy agents for multiple cancer types. To date, no reliable predictors of activity and efficacy of immunotherapy have yet been identified or validated. Even so, determining which patients derive clinical benefit from immune checkpoint agents remains an important clinical question and efforts to identify predictive markers of response are ongoing. This article reviews the current potential predictive factors for CTLA-4 and PD-1/PD-L1 immune checkpoints inhibitors in melanoma.
Project description:The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed.
Project description:Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell death protein-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anticytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), which have been approved for treating different types of malignancies. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host-tumor interaction. There are several the US food and drug administration (FDA)-approved ICIs targeting PD-1, including pembrolizumab and nivolumab, as well as those targeting PD-L1, including avelumab, atezolizumab, and durvalumab for melanoma, renal cell cancer, colorectal cancer, head and neck cancer, cervix cancer, urothelial cancer, and lung cancer. Current pre-clinical and clinical studies assessing PD-1/PD-L1 inhibitors in several gynecologic cancers have reported significant antitumor activity. In this review, we investigate pre-clinical and clinical studies that describe the safety and efficacy of anti-PD-1/PD-L1 antibodies, with a particular focus on ongoing clinical trials, analyzing the oncological outcome and adverse effects of ICIs in gynecologic cancers.