Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway (original) (raw)
Related papers
Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer
New England Journal of Medicine, 2012
Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients-75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer-had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. Conclusions Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.
Cancers, 2018
Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs) might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1), and its ligand, programmed death-ligand 1 (PD-L1), via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully id...
Acta Scientific Microbiology, 2021
Immune checkpoints are a group of inhibitory mechanisms that are encoded into the immune system. Mice treated with anti-PD L1 or PD-1-deficient animals showed increased tumorigenesis and invasiveness in syngeneic hosts when compared to parental tumor cells lacking PD-L. The classical type of programmed cell death is distinguished by its morphological hallmarks of apoptosis and its reliance on de novo RNA and protein production. The PD-1 gene was active in both stimulated 2B4.11 and IL-3-depleted LyD9 cells. The findings imply that the genetic landscape of lung malignancies influences anti-PD-1 therapeutic responsiveness. Immune resistance can be overcome by blocking the inhibitory receptor programmed death 1 (PD-1), which is produced by T cells. An antibody that precisely targets PD-1, was considered for anticancer efficacy and safety. There is a link between PD-L1 expression on tumor cells and objective response. In patients with advanced malignancies such as non-small cell lung cancer, melanoma, and renalcell cancer, antibody-mediated PD-L1 inhibition resulted in long-term tumor shrinkage and disease stability.
PD-1, PD-L1 mechanism and cancer treatment
2021
In response to a foreign organism or material, our bodies react with a variety of immunological agents. This response mechanism is called immunogenicity. While some of the proteins that regulate the immune response function to activate this response, some of them are responsible for inhibiting this response. The main "brake" proteins involved in this negative regulation are cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein-1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein-3, and lymphocyte-activation gene-3. The cell can differentiate endogenous and exogenous substances through these brakes and other signal pathways. In the presence of brake proteins, the tumor cells are not perceived as a threat by the immune system, so a corresponding response does not occur. To generate this response, drugs containing monoclonal antibodies are produced for use in cancer treatments. Monoclonal antibodies are designed to block braking processes while also eliciting an immunological response. In this review, the PD-1 and programmed cell death-ligand 1 pathway and cancer immunotherapy are mentioned.
PD-L1 Distribution and Perspective for Cancer Immunotherapy—Blockade, Knockdown, or Inhibition
Frontiers in Immunology
Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. However, this therapy has limited effects on many solid tumors, suspecting to be relevant to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. In this review, we highlight the advances of 3 current strategies on PD-1/PD-L1 based immunotherapy, summarize cellular distribution of PD-L1, and review the versatile functions of intracellular PD-L1. The intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.
Review Article Current and Future Perspectives of PD-1/PDL-1 Blockade in Cancer Immunotherapy
2021
Cancer immunotherapy, which reactivates weakened immune cells of cancer patients, has yielded great success in recent years. Among immunotherapeutic agents, immune checkpoint inhibitors have been of particular interest and have gained approval by the FDA for treatment of cancers. Immune checkpoint blockade through targeting programmed cell death protein-1 (PD-1) has demonstrated promising antitumor effects in cancer immunotherapy of many different solid and hematologic malignancies. However, despite promising results, a favorable response is observed only in a fraction of patients, and there is still lack of a single therapy modality with curative ability. In this paper, we review the current and future perspectives of PD-1/L1 blockade in cancer immunotherapy, with a particular focus on predictive biomarkers of response to therapy. We also discuss the adverse events associated with PD-1/L1/2 inhibitors, ranging from severe life-threatening conditions such as autoimmune myocarditis to mild and moderate reactions such as skin rashes, and explore the potential strategies for improving the efficacy of immunotherapy with PD-1/L1 checkpoint inhibitors.
Seven different anti-PD-1 and PD-L1 monoclonal antibodies are now widely used in the US to treat a variety of cancer types, but there have been no clinical trials comparing them directly. Furthermore, because many of these antibodies do not cross react between mouse and human proteins, no preclinical models exist in which to consider these types of questions. Thus, we produced humanized PD-1 and PD-L1 mice in which the extracellular domains of both mouse PD-1 and PD-L1 were replaced with the corresponding human sequences. Using this new model, we sought to compare the strength of the immune response generated by FDA-approved antibodies. To do this, we performed an in vivo T cell priming assay in which anti-PD-1/L1 therapies were given at the time of T cell priming against surrogate tumor antigen (OVA), followed by subsequent B16-OVA tumor challenge. We found that anti-PD-1/L1-treated mice exhibited significantly better tumor rejection than controls, although both the control and ant...
Immune Checkpoint Inhibitors - New Insights and Recent Progress [Working Title]
Monoclonal antibodies that inhibit “immune checkpoint” through programmed cell death-1 and its ligand (PD-1/PD-L1) blockage have proven remarkable therapeutic action toward a range of cancer types. Hence, immunotherapy, binding the immune system to act against malignant tumors, has generated encouraging outcomes in clinical practice. Nevertheless, the robust advantage is not observed in a large number of patients. Recognizing patients that will probably respond and using therapies covering a larger number of patients necessitate an enhanced understanding of the biological action of PD-1 and cytotoxic T lymphocyte antigen (CTLA) at the cell level and reviewing the performed clinical studies and their outcomes to recognize the accumulating proof of its clinical significance. In this chapter, we will discuss and review the clinical and preclinical data regarding Immune Checkpoint Inhibitors PD-1/PD-L1 to recognize the advances and challenges of their implication in clinical practice.
Current and Future Perspectives of PD-1/PDL-1 Blockade in Cancer Immunotherapy
Journal of Immunology Research
Cancer immunotherapy, which reactivates weakened immune cells of cancer patients, has yielded great success in recent years. Among immunotherapeutic agents, immune checkpoint inhibitors have been of particular interest and have gained approval by the FDA for treatment of cancers. Immune checkpoint blockade through targeting programmed cell death protein-1 (PD-1) has demonstrated promising antitumor effects in cancer immunotherapy of many different solid and hematologic malignancies. However, despite promising results, a favorable response is observed only in a fraction of patients, and there is still lack of a single therapy modality with curative ability. In this paper, we review the current and future perspectives of PD-1/L1 blockade in cancer immunotherapy, with a particular focus on predictive biomarkers of response to therapy. We also discuss the adverse events associated with PD-1/L1/2 inhibitors, ranging from severe life-threatening conditions such as autoimmune myocarditis t...