Combination immuno-oncology therapy with immune checkpoint blockers targeting PD-L1, PD-1 or CTLA4 and epigenetic drugs targeting MYC and immune evasion for precision medicine.
Combination immuno-oncology therapy with immune checkpoint blockers targeting PD-L1, PD-1 or CTLA4 and epigenetic drugs targeting MYC and immune evasion for precision medicine.
Project description:Immune checkpoint inhibitors are designed to restore a patient's own antitumor immune response that has been suppressed during tumor development. The first monoclonal antibodies against the immune checkpoint programmed death 1 (PD-1) receptor, nivolumab and pembrolizumab, are now approved for clinical use. Both agents are indicated for the treatment of advanced melanoma, as well as for the treatment of metastatic non-small cell lung cancer (NSCLC). Nivolumab is also approved for the treatment of advanced renal cell carcinoma. In patients with melanoma, these agents result in objective response rates of ~25-40%, with durable responses lasting more than 2 years in some cases. Results from phase III trials have shown improved survival with nivolumab versus standard-of-care chemotherapy in both patients with advanced melanoma and those with advanced NSCLC. In patients with advanced melanoma, both PD-1 inhibitors (nivolumab and pembrolizumab) have shown improved survival versus ipilimumab. PD-1 inhibitors are associated with adverse events that have immune etiologies, with grade greater than 3 adverse events typically reported in 16% or less of patients. However, most immune-mediated adverse events (including grade 3-4 adverse events) can be managed by using published management algorithms without permanent discontinuation of the agent. As nivolumab and pembrolizumab enter the clinic, and with more PD-1 pathway agents in development for a range of tumor types, this review aims to provide pharmacists with a basic understanding of the role of PD-1 in modulating the immune system and their use in the cancer treatment. The most recent clinical efficacy and safety data are discussed, highlighting the response characteristics distinctive to immune checkpoint inhibitors, along with pharmacokinetic and pharmacodynamic data and cost considerations.
Project description:Cancer cells can evade immune surveillance through the molecular interactions of immune checkpoint proteins, including programmed death 1 (PD-1), PD-L1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Since 2011, the FDA-approved antibody drugs ipilimumab (Yervoy®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®), atezolizumab (Tecentriq®), durvalumab (Imfinzi®), and avelumab (Bavencio®), which block the immune checkpoint proteins, have brought about a significant breakthrough in the treatment of a wide range of cancers, as they can induce durable therapeutic responses. In recent years, crystal structures of the antibodies against PD-1, PD-L1, and CTLA-4 have been reported. In this review, we describe the latest structural studies of these monoclonal antibodies and their interactions with the immune checkpoint proteins. A comprehensive analysis of the interactions of these immune checkpoint blockers can provide a better understanding of their therapeutic mechanisms of action. The accumulation of these structural studies would provide a basis that is essential for the rational design of next-generation therapies in immuno-oncology.
Project description:Since the dawn of the past century, landmark discoveries in cell-mediated immunity have led to a greater understanding of the innate and adaptive immune systems and revolutionised the treatment of countless diseases, including cancer. Today, precision immuno-oncology (I/O) involves not only targeting immune checkpoints that inhibit T-cell immunity but also harnessing immune cell therapies. The limited efficacy in some cancers results mainly from a complex tumour microenvironment (TME) that, in addition to adaptive immune cells, comprises innate myeloid and lymphoid cells, cancer-associated fibroblasts, and the tumour vasculature that contribute towards immune evasion. As the complexity of TME has called for more sophisticated human-based tumour models, organoids have allowed the dynamic study of spatiotemporal interactions between tumour cells and individual TME cell types. Here, we discuss how organoids can study the TME across cancers and how these features may improve precision I/O. We outline the approaches to preserve or recapitulate the TME in tumour organoids and discuss their potential, advantages, and limitations. We will discuss future directions of organoid research in understanding cancer immunology in-depth and identifying novel I/O targets and treatment strategies.
Project description:Immune checkpoint blockade therapies (ICBTs) targeting programmed cell death 1 (PD-1) and its ligand programmed death ligand-1 (PD-L1/B7-H1/CD274) have exhibited momentous clinical benefits and durable responses in multiple tumor types. However, primary resistance is found in considerable number of cancer patients, and most responders eventually develop acquired resistance to ICBT. To tackle these challenges, it is essential to understand how PD-L1 is controlled by cancer cells to evade immune surveillance. Recent research has shed new light into the mechanisms of PD-L1 regulation at genetic, epigenetic, transcriptional, translational, and posttranslational levels. In this work, we systematically discuss the mechanisms that control the gene amplification, epigenetic alteration, transcription, subcellular transportation and posttranscriptional modification of PD-L1 in cancer cells. We further categorize posttranscriptional PD-L1 regulations by the molecular modification of PD-L1, including glycosylation, phosphorylation, ubiquitination, deubiquitination, and lysosomal degradation. These findings may provide new routes for targeting tumor immune escape and catalyze the development of small molecular inhibitors of PD-L1 in addition to existing antibody drugs.
Project description:Immunotherapy, based on immune checkpoint inhibitors targeting the Programmed cell death ligand 1 (PD-L1) and/or Programmed Death Receptor 1 (PD-1), has substantially improved the outcomes of patients with various cancers. However, only ~30% of patients benefit from immune checkpoint inhibitors. Tumor PD-L1 expression, assessed by immunohistochemistry, is the most widely validated and used predictive biomarker to guide the selection of patients for immune checkpoint inhibitors. PD-L1 assessment may be challenging due to the necessity for different companion diagnostic assays for required specific immune checkpoint inhibitors and a relatively high level of inter-assay variability in terms of performance and cutoff levels. In this review, we discuss the role of PD-L1 immunohistochemistry as a predictive test in immunotherapy (immuno-oncology), highlight the complexity of the PD-L1 testing landscape, discuss various preanalytical, analytical and clinical issues that are associated with PD-L1 assays, and provide some insights into optimization of PD-L1 as a predictive biomarker in immuno-oncology.
Project description:The years since 2009 have seen tremendous progress in unlocking the curative potential of the immune system for the treatment of cancer. Much of that revolution in immuno-oncology has been fueled by the clinical success of immune checkpoint inhibitors, particularly those targeting the PD-1 axis. Unfortunately, many patients still fail to benefit from checkpoint blockade or other immunotherapies. An inability to fully activate antitumour T cells contributes in part to the failure of those therapies. Here, we review the basic biology of T cell activation, with particular emphasis on the essential role of the dendritic cell and the innate immune system in T cell activation. The current understanding of the multiple factors that govern T cell activation and how they impinge on tumour immunotherapy are also discussed. Lastly, treatment strategies to potentially overcome barriers to T cell activation and to enhance the efficacy of immunotherapy are addressed.
Project description:Pancreatic malignancies carry a dismal prognosis globally, with pancreatic adenocarcinomas (PDAC) being particularly aggressive and stubborn. Unfortunately, several therapeutic strategies that show promise in other cancers have failed to make sizeable impact on pancreatic tumor outcomes. Responses to immunotherapies are especially rare in pancreatic cancer, and patients are in need of innovative approaches that can result in more durable responses. Current research in preclinical models and humans has suggested this resistance is due to a uniquely inflammatory and dysfunctional tumor microenvironment; these findings lay the groundwork for targeting these barriers and improving outcomes. Clinical analyses have also revealed unprecedented heterogeneity in tumor and stromal biology of PDAC, underscoring the need for more personalized approaches and combinatorial therapies. This review will highlight the current state of translational research focusing on PDAC immunity, summarize ongoing clinical efforts to tackle PDAC vulnerabilities, and underscore some unresolved challenges in implementing therapies more broadly. A better understanding of immune contexture and tumor heterogeneity in this disease will greatly accelerate drug discovery and implementation of precision medicine for PDAC.
Project description:Viruses often subvert antiviral immune responses by taking advantage of inhibitory immune signaling. We investigated if hantaviruses use this strategy. Hantaviruses cause viral hemorrhagic fever (VHF) which is associated with strong immune activation resulting in vigorous CD8+ T cell responses. Surprisingly, we observed that hantaviruses strongly upregulate PD-L1 and PD-L2, the ligands of checkpoint inhibitor programmed death-1 (PD-1). We detected high amounts of soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2) in sera from hantavirus-infected patients. In addition, we observed hantavirus-induced PD-L1 upregulation in mice with a humanized immune system. The two major target cells of hantaviruses, endothelial cells and monocyte-derived dendritic cells, strongly increased PD-L1 and PD-L2 surface expression upon hantavirus infection in vitro. As an underlying mechanism, we found increased transcript levels whereas membrane trafficking of PD-L1 was not affected. Further analysis revealed that hantavirus-associated inflammatory signals and hantaviral nucleocapsid (N) protein enhance PD-L1 and PD-L2 expression. Cell numbers were strongly reduced when hantavirus-infected endothelial cells were mixed with T cells in the presence of an exogenous proliferation signal compared to uninfected cells. This is compatible with the concept that virus-induced PD-L1 and PD-L2 upregulation contributes to viral immune escape. Intriguingly, however, we observed hantavirus-induced CD8+ T cell bystander activation despite strongly upregulated PD-L1 and PD-L2. This result indicates that hantavirus-induced CD8+ T cell bystander activation bypasses checkpoint inhibition allowing an early antiviral immune response upon virus infection.
Project description:Current tumor thermal ablation techniques rely on extreme temperatures to induce irreversible cellular injury and coagulative tissue necrosis. Ablation-induced cellular injury or death releases cancer neoantigens and activates the cancer-immunity cycle, potentially generating tumor-specific immune effectors. However, multiple negative regulatory modulators exist at each step of the cycle, mitigating meaningful and therapeutic anticancer effect provided by the immune system. Recent studies have focused on the introduction and testing of adjuvant immunotherapy combined with ablation to synergistically shift the equilibrium out of inhibitory immune modulation. This article reviews the immune microenvironment in relation to image-guided ablation techniques and discusses current and upcoming novel strategies to take advantage of antitumor immunity.