Showing papers in "Immunotherapy in 2016"
TL;DR: The possibility that IL-6 blockade may constitute a novel therapeutic strategy for other types of cytokine storm, such as the systemic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis is proposed.
Abstract: IL-6 contributes to host defense against infections and tissue injuries. However, exaggerated, excessive synthesis of IL-6 while fighting environmental stress leads to an acute severe systemic inflammatory response known as ‘cytokine storm’, since high levels of IL-6 can activate the coagulation pathway and vascular endothelial cells but inhibit myocardial function. Remarkable beneficial effects of IL-6 blockade therapy using a humanized anti-IL-6 receptor antibody, tocilizumab were recently observed in patients with cytokine release syndrome complicated by T-cell engaged therapy. In this review we propose the possibility that IL-6 blockade may constitute a novel therapeutic strategy for other types of cytokine storm, such as the systemic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis.
518 citations
TL;DR: Reliable biomarkers are necessary to define patients who will achieve best clinical benefit with minimal toxicity in combination therapy, and potential synergistic combinations include checkpoint blockade with conventional therapies and newer immunotherapies.
Abstract: The emergence of immune ‘checkpoint inhibitors’ such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) has revolutionized treatment of solid tumors including melanoma, lung cancer, among many others. The goal of checkpoint inhibitor combination therapy is to improve clinical response and minimize toxicities. Rational design of checkpoint combinations considers immune-mediated mechanisms of antitumor activity: immunogenic cell death, antigen release and presentation, activation of T-cell responses, lymphocytic infiltration into tumors and depletion of immunosuppression. Potential synergistic combinations include checkpoint blockade with conventional (radiation, chemotherapy and targeted therapies) and newer immunotherapies (cancer vaccines, oncolytic viruses, among others). Reliable biomarkers are necessary to define patients who will achieve best clinical benefit with minimal toxicity in combination therapy.
133 citations
TL;DR: PD-L1 overexpression could not be currently considered a robust biomarker to tailor the immune checkpoint inhibitors treatment, according to Cochrane Collaboration's Guidelines.
Abstract: Background: Tumor programmed death ligand one (PD-L1) expression has been studied in several trials in non-small-cell lung cancer. Methods: We assessed the potential role of PD-L1 expression according to Cochrane Collaboration's Guidelines. Results: 13 studies with 1979 patients were included. Among 915 PD-L1 negative patients this rate was 13% (RR 2.08; 95% CI: 1.49–2.91; p < 0.01). The response rate has increased concurrent to the PD-L1 expression (Pearson's correlation, r = 0.43). PD-L1 expression was also related to better 24-weeks progression-free rate (RR 0.79; 95% CI: 0.71–0.89) and a trend toward better 1-year overall survival rate (RR 0.96; 95% CI: 0.87–1.06). Conclusion: Taking this data in account, PD-L1 overexpression could not be currently considered a robust biomarker to tailor the immune checkpoint inhibitors treatment.
128 citations
TL;DR: chieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.
Abstract: Hepatocellular carcinoma (HCC) is a fatal disease with rising incidence in the world. For advanced HCC, sorafenib, a multikinase inhibitor, is the only systemic therapy with proven survival benefits. Sorafenib is a pan-VEGF receptor inhibitor, and thus many studies have focused its antivascular effects. But VEGF also acts as an immunosuppressive molecule. VEGF can inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. On the other hand, potent VEGF inhibition may increase tumor hypoxia, which could hinder antitumor immunity or immunotherapy. Thus, achieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.
125 citations
TL;DR: Preclinical and clinical studies in which intravenous or mucosal administration of anti-CD3 mAbs has been employed are reviewed and an outlook on future developments to enhance the efficacy of this promising therapeutic approach is provided.
Abstract: The induction of tolerance is a major goal of immunotherapy. Investigations over the last 20 years have shown that anti-CD3 monoclonal antibodies (mAbs) effectively treat autoimmune disease in animal models and have also shown promise in clinical trials. Tolerance induction by anti-CD3 mAbs is related to the induction of Tregs that control pathogenic autoimmune responses. Here, we review preclinical and clinical studies in which intravenous or mucosal administration of anti-CD3 mAbs has been employed and provide an outlook on future developments to enhance the efficacy of this promising therapeutic approach.
122 citations
TL;DR: The fundamental, preclinical and clinical findings related to the role of the CD73-adenosinergic pathway in tumor immunity are discussed.
Abstract: Cancer immunotherapy has entered in a new era with the development of first-generation immune checkpoint inhibitors targeting the PD1/PD-L1 and CTLA-4 pathways. In this context, considerable research effort is being deployed to find the next generation of cancer immunotherapeutics. The CD73-adenosine axis constitutes one of the most promising pathways in immuno-oncology. We and others have demonstrated the immunosuppressive role of CD73-adenosine in cancer and established proof-of-concept that the targeted blockade of CD73 or adenosine receptors could effectively promote anti-tumor immunity and enhance the activity of first-generation immune checkpoint blockers. With Phase I clinical trials now underway evaluating anti-CD73 or anti-A2A therapies in cancer patients, we here discuss the fundamental, preclinical and clinical findings related to the role of the CD73-adenosinergic pathway in tumor immunity.
112 citations
TL;DR: This work reviews the many approaches that have attempted to accomplish effective in situ vaccination, using intratumoral administration of immunomodulators to increase the numbers or activation state of either antigen present cells or T cells within the tumor.
Abstract: Vaccination has had a tremendous impact on human health by harnessing the immune system to prevent and eradicate infectious diseases and this same approach might be used in cancer therapy. Cancer vaccine development has been slowed hindered by the paucity of universal tumor-associated antigens and the difficulty in isolating and preparing individualized vaccines ex vivo. Another approach has been to initiate or stimulate an immune response in situ (at the tumor site) and thus exploit the potentially numerous tumor-associated antigens there. Here, we review the many approaches that have attempted to accomplish effective in situ vaccination, using intratumoral administration of immunomodulators to increase the numbers or activation state of either antigen present cells or T cells within the tumor.
69 citations
TL;DR: This review will focus on the tumor immune microenvironment, the expression of PD-1/PD-L1 and the effect of immune modulation using PD- 1 or PD- L1 inhibitors in patients with head and neck, prostate, urothelial, renal, breast, gastrointestinal and lung cancers.
Abstract: Immune checkpoint inhibitors have been identified as breakthrough treatment in melanoma given its dramatic response to PD-1/PD-L1 blockade. This is likely to extend to many other cancers as hundreds of clinical trials are being conducted or proposed using this exciting modality of therapy in a variety of malignancies. While immune checkpoint inhibitors have been extensively studied in melanoma and more recently in lung cancer, little is known regarding immune checkpoint blockade in other cancers. This review will focus on the tumor immune microenvironment, the expression of PD-1/PD-L1 and the effect of immune modulation using PD-1 or PD-L1 inhibitors in patients with head and neck, prostate, urothelial, renal, breast, gastrointestinal and lung cancers.
64 citations
TL;DR: Given the growing rate of approval of different checkpoint inhibitors in different cancers in multiple settings, a review summarizing the major side effects of the new agents in use today and their management seems to be appropriate.
Abstract: The next decade in cancer therapy will be marked by the expansion of immunotherapies, namely immune checkpoint inhibitors. The increasing number and combination of checkpoint inhibitors and the variety of their mechanisms of action and indications will most likely multiply the side effects associated with these therapies and make their management more complicated and diversified. Given the growing rate of approval of different checkpoint inhibitors in different cancers in multiple settings, a review summarizing the major side effects of the new agents in use today and their management seems to be appropriate. Highlighting these adverse events and their management in a single review might help the daily practice of the physicians and consequently contribute the patient's safety and quality of life.
62 citations
TL;DR: The rationale for using Mesothelin as a target for immunotherapy is outlined, the clinical and preclinical studies evaluating mesothelin-directed therapies are reviewed, and the promise of CAR T cells directed against mesothelioma and pancreatic and ovarian cancers in the future are explored.
Abstract: Mesothelin is a promising target for immune-based therapy, specifically for mesothelioma and pancreatic and ovarian cancers that have high levels of mesothelin expression. Many preclinical and clinical studies that target tumors with high mesothelin expression with antibodies, immunotoxins, antibody-drug conjugates and vaccines have shown the potential of mesothelin as a target. Studies of T cells genetically modified with chimeric antigen receptors (CAR) report significant efficacy in hematologic malignancies, and antimesothelin CAR T cells are currently being investigated in clinical studies. Here we outline the rationale for using mesothelin as a target for immunotherapy, review the clinical and preclinical studies evaluating mesothelin-directed therapies and explore the promise of CAR T cells directed against mesothelin for immunotherapy in the future.
61 citations
TL;DR: After the recent impressive results in animal studies obtained by salsalate, the dimer of salicylic acid, inhibitors of tau acetylation are being actively pursued.
Abstract: Pharmacological manipulation of tau protein in Alzheimer's disease included microtubule-stabilizing agents, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies and, more recently, inhibitors of tau acetylation. Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function. Two active vaccines targeting either nonphosphorylated (AAD-vac1) and phosphorylated tau (ACI-35) have entered Phase I testing. Notwithstanding, the recent discontinuation of the monoclonal antibody RG7345 for Alzheimer's disease, two other antitau antibodies, BMS-986168 and C2N-8E12, are also currently in Phase I testing for progressive supranuclear palsy. After the recent impressive results in animal studies obtained by salsalate, the dimer of salicylic acid, inhibitors of tau acetylation are being actively pursued.
TL;DR: This review describes the current understanding regarding epigenetic and immunotherapy combination, focusing on immune response priming to checkpoint blockade.
Abstract: Immune surveillance should be directed to suppress tumor development and progression, involving a balance of coinhibitory and costimulatory signals that amplify immune response without overwhelming the host. Immunotherapy confers durable clinical benefit in ‘immunogenic tumors’, whereas in other tumors the responses are modest. Thus, immune checkpoint inhibitors may need to be combined with strategies to boost immune response or increase the tumor immune profile. Epigenetic aberrations contribute significantly to carcinogenesis. Recent findings suggest that epigenetic drugs prime the immune response by increasing expression of tumor-associated antigens and immune-related genes, as well as modulating chemokines and cytokines involved in immune system activation. This review describes our current understanding regarding epigenetic and immunotherapy combination, focusing on immune response priming to checkpoint blockade.
TL;DR: Novel therapies are now investigating combining checkpoint inhibitors with chemotherapy, targeted therapy, radiation and vaccines to produce synergistic antitumor activity.
Abstract: The role of immunotherapy in treatment of non-small-cell lung cancer (NSCLC) has been gaining interest over the past few years. This has been driven primarily by promising results from trials evaluating antagonist antibodies that target co-inhibitory immune checkpoints expressed on tumor cells and immune cells within the tumor microenvironment. Immune checkpoints exist to dampen or terminate immune activity to guard against autoimmunity and allow for self-tolerance. However, tumors can take advantage of these immune checkpoint pathways to evade destruction. Antibodies that block inhibitory checkpoints, such as anti-CTLA-4, anti-PD1 and anti-PD-L1 antibodies have demonstrated delayed tumor growth and increased survival. Novel therapies are now investigating combining checkpoint inhibitors with chemotherapy, targeted therapy, radiation and vaccines to produce synergistic antitumor activity.
TL;DR: Crisaborole Topical Ointment, 2%, is a novel, nonsteroidal, topical anti-inflammatory PDE4 inhibitor currently being investigated for the treatment of mild to moderate AD.
Abstract: Atopic dermatitis (AD), a chronic, relapsing, inflammatory skin disease that is characterized by intense pruritus and eczematous lesions with up to 90% of patients presenting with mild to moderate disease. Current topical treatments for AD have not changed in over 15 years and are associated with safety concerns. In AD, overactivity of phosphodiesterase 4 (PDE4), leads to inflammation and disease exacerbation. Crisaborole Topical Ointment, 2%, is a novel, nonsteroidal, topical anti-inflammatory PDE4 inhibitor currently being investigated for the treatment of mild to moderate AD. Preliminary studies in children and adults demonstrated favorable efficacy and safety profiles. Crisaborole may represent an anti-inflammatory option that safely minimizes the symptoms and severity of AD and that can be used for both acute and long-term management.
TL;DR: The role of antibody-targeted NPs in the treatment of cancer: as delivery vehicles, targeted theranostic agents and in the evolving field of cancer hyperthermia is discussed.
Abstract: Nanoparticles (NPs) are diverse and versatile with physical properties that can be employed for use in cancer medicine. Targeting NPs using antibodies and antibody fragments could overcome some of the limitations seen with current targeted therapies. This review will discuss the role of antibody-targeted NPs in the treatment of cancer: as delivery vehicles, targeted theranostic agents and in the evolving field of cancer hyperthermia.
TL;DR: Different mAb-based strategies that capitalize on the targeting ability of anti-GD2 mAbs to potentially deliver, as monotherapy, or in combination with other treatments, improved antitumor efficacy are discussed.
Abstract: Tumor-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the clinic, becoming an important approach for cancer immunotherapy. Due to its limited expression on normal tissue, the GD2 disialogangloside expressed on neuroblastoma cells is an excellent candidate for mAb therapy. In 2015, dinutuximab (an anti-GD2 mAb) was approved by the US FDA and is currently used in a combination immunotherapeutic regimen for the treatment of children with high-risk neuroblastoma. Here, we review the extensive preclinical and clinical development of anti-GD2 mAbs and the different mechanisms by which they mediate tumor cell killing. In addition, we discuss different mAb-based strategies that capitalize on the targeting ability of anti-GD2 mAbs to potentially deliver, as monotherapy, or in combination with other treatments, improved antitumor efficacy.
TL;DR: Changes in LDH level and side effects correlate with response to therapy and survival, and was significantly negatively correlated with treatment response and overall survival and progression-free survival.
Abstract: Background: Ipilimumab is a cytotoxic T-lymphocyte antigen-4 antibody that enhances T-cell activity and proliferation. Methods: In a retrospective analysis of 86 patients the clinical benefits of ipilimumab treatment were correlated with laboratory and clinical data. Results: A lactate dehydrogenase (LDH) value within the normal range before the start of therapy was significantly correlated with better OS (p ≤ 0.009). An increase in LDH level after two cycles was indicative of a poor outcome, and was significantly negatively correlated with treatment response and overall survival and progression-free survival. 42% of all patients suffered from autoimmune toxicity (CTCAE grades 2–4). The occurrence of autoimmune toxicity clearly correlated with clinical benefit. Conclusion: Changes in LDH level and side effects correlate with response to therapy and survival.
TL;DR: The therapeutic trials of blocking these pathways in human lung cancer and hematological malignancies are reviewed and the duration of responders due to immunological memory is remarkable and is longer than would be expected with any other agent in refractory disease.
Abstract: Tumor immune evasion is one of the hallmarks of cancer, and expression of the B7 family of immune checkpoints (PD-L1, PD-L2, B7-H3, B7x and HHLA2) is one mechanism of immune evasion by tumors to suppress T-cell function. Antibodies blocking these interactions of B7-1/B7-2/CTLA-4 and PD-L1/PD-L2/PD-1 have had remarkable clinical success in several cancers and are less toxic than traditional chemotherapy. Even though only a small proportion of patients respond to checkpoint blockade, the duration of such responders due to immunological memory is remarkable and is longer than would be expected with any other agent in refractory disease. In this article, we review the therapeutic trials of blocking these pathways in human lung cancer and hematological malignancies.
TL;DR: A recent trial of PD-1 inhibition in patients with tumors with high mutational load has shown dramatic and durable responses, even in patientsWith colon cancer, and suggests a shifting mode of patient selection based not on tumor type, but upon molecular signature.
Abstract: Efficacy of PD-1 blockade in tumors with MMR deficiency Immune checkpoint blockade has become a new option in clinical practice with US FDA approvals of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) inhibitors in melanoma and squamous cell lung cancer. Broader use of these well-tolerated PD-1 inhibitors becomes more likely as evidence of activity accumulates in many other tumor types including head and neck, gastroesophageal, renal cell, small cell lung and bladder cancer. Studies in previously treatment refractory patients with these cancers have shown response rates to PD-1 inhibitors of up to 20–30% (and higher responses in selected subsets), including a number of durable responses of months to years [1–3]. Despite these advances, PD-1 inhibition in other disease histologies such as colorectal cancer (CRC) and pancreaticobiliary cancers has been negligible. The rare exceptional responder may lend insight into a subset of susceptible patients and i dentification of predictive biomarkers. The PD-1 pathway (consisting of the PD-1 receptor and its ligands PD-L1 and PD-L2) are found on a number of immune cells, including activated T cells, B-cells, NK cells, monocytes and dendritic cells. The inhibitory antibodies against PD-1 currently on the market include pembrolizumab (Keytruda) and nivolumab (Opdivo). Normal activation of the PD-1 pathway leads to suppression of immune function by modification of cytokine production and suppression of activated T-cells. This pathway is overexpressed in a number of tumors, leading to development of immune tolerance and tumor evasion. PD-L1 overexpression has been correlated with worsened survival, but allows for an intriguing target by allowing reinstatement of the normal immune function. Tumors with more antigenicity are presumed better targets for immune modulation, and so virally-mediated tumors and those with high mutational load are among the tumor subsets that are being explored [4]. These groups both result in enhanced production of antigens, which are more likely to be presented as ‘nonself ’ to T cells, potentially overcoming tolerance, and enhancing an immune attack. A recent trial of PD-1 inhibition in patients with tumors with high mutational load has shown dramatic and durable responses, even in patients with colon cancer, and suggests a shifting mode of patient selection based not on tumor type, but upon molecular signature [5].
TL;DR: Robert Coffin is co-founder and CEO of Replimune and the inventor of all BioVex products including OncoVEXGM-CSF and oversaw all research and clinical development including bringing T-VEC through to two pivotal Phase 3 studies in melanoma and head and neck cancer.
Abstract: Interviewed by Ellen Clarke, Commissioning Editor, Future Science Group. Robert Coffin is co-founder and CEO of Replimune. Previously he was Founder and CTO of BioVex Inc, a spin out from his research group at University College London in 1999. He was the inventor of all BioVex products including OncoVEXGM-CSF (talimogene laherparepvec; T-VEC; Imlygic) and oversaw all research and clinical development including bringing T-VEC through to two pivotal Phase 3 studies in melanoma and head and neck cancer. BioVex was acquired by Amgen in 2011 where he was VP Global Development until 2013. T-VEC was approved by the FDA for use in advanced melanoma in October 2015, the first oncolytic therapy or gene therapy to be approved in USA. He was awarded a PhD in virology from Imperial College London prior to his move to University College London in 1991.
TL;DR: It is demonstrated that the use of immune checkpoint inhibitors is associated with an increased risk of all-grade immune-related renal toxicity compared with chemotherapy control.
Abstract: Background: We performed a network meta-analysis of the risk of immune-related renal toxicity associated with immune checkpoint inhibitors. Methods: Eligible studies included randomized trials of patients with immune checkpoint inhibitors; describing events of immune-related renal toxicity. Results: Compared with chemotherapy control, immune checkpoint inhibitors carry a higher risk of all-grade (but not high-grade) immune-related renal toxicity. The risk with both nivolumab/ipilimumab combination was higher than the risk with either ipilimumab or nivolumab alone (odds ratio: 0.47 [95% credible interval: 0.21–0.99] and 0.11 [95% credible interval: 0.03–0.29]); for nivolumab/ipilimumab combination versus ipilimumab or nivolumab monotherapy). Conclusion: Our meta-analysis demonstrated that the use of immune checkpoint inhibitors is associated with an increased risk of all-grade immune-related renal toxicity compared with chemotherapy control.
TL;DR: This paper summarizes existing data supporting the use of immune therapies in osteosarcoma and the progress of this class of drugs in ostea therapy and describes the discovery of novel immune checkpoint blockade strategies and their success in adult cancers.
Abstract: Survival outcomes for osteosarcoma have plateaued since the 1980s, and patients with relapsed or refractory disease have a particularly dismal outcome. Treatment options for these patients are limited primarily due to the paucity of effective therapeutics. Immune therapies such as tumor vaccines and traditional antigen-targeted monoclonal antibodies have had limited success in solid tumors. The recent discovery of novel immune checkpoint blockade strategies and their success in adult cancers has revitalized the use of immunotherapy strategies for the treatment of solid tumors. This paper summarizes existing data supporting the use of immune therapies in osteosarcoma and the progress of this class of drugs in osteosarcoma therapy.
TL;DR: These combination therapies are of clinical interest because they could lower the threshold for IL-12 efficacy, increasing the therapeutic potential of gene therapy and preventing the toxicity mediated by this cytokine.
Abstract: IL-12 is an immunostimulatory cytokine with strong antitumor properties. Systemic administration of IL-12 in cancer patients led to severe toxic effects, prompting the development of gene therapy vectors able to express this cytokine locally in tumors. Both nonviral and viral vectors have demonstrated a high antitumor efficacy in preclinical tumor models. Some of these vectors, including DNA electroporation, adenovirus and ex vivo transduced dendritic cells, were tested in patients, showing low toxicity and moderate antitumor efficacy. IL-12 activity can be potentiated by molecules with immunostimulatory, antiangiogenic or cytotoxic activity. These combination therapies are of clinical interest because they could lower the threshold for IL-12 efficacy, increasing the therapeutic potential of gene therapy and preventing the toxicity mediated by this cytokine.
TL;DR: The available data reinforce nivolumab activity against NSCLC in first-line or subsequent lines, and indicate that PD-L1 expression is related to greater response, and PD- L1 negative patients had also some benefit.
Abstract: Background: Recent studies with nivolumab (a monoclonal antibody against programmed cell death 1 [PD-1] receptor) have shown promise non-small-cell lung cancer (NSCLC) treatment. Methods: To review available clinical trials data in order to assess nivolumab efficacy and the role of tumoral PDL-1 expression as a biomarker. Results: Nine eligible studies included 2102 patients. In the second line setting, nivolumab achieved a 1-year survival rate of 41%; and in the first line, a 1-year survival rate of 76%. For those with PD-L1 expression <1%, nivolumab showed a trend for improved survival compared with docetaxel. Conclusions: The available data reinforce nivolumab activity against NSCLC in first-line or subsequent lines. Although PD-L1 expression is related to greater response, PD-L1 negative patients had also some benefit.
TL;DR: The current analysis indicates the value of PD-L 1 positivity in predicting higher response from PD-1/PD-L1 agents and may help further individualize treatment options for metastatic melanoma patients.
Abstract: Aim: This meta-analysis aims at assessing the correlation of PD-L1 levels and response PD-1/PD-L1 inhibitors in advanced malignant melanoma. Methods: Eligible studies included those evaluating PD-1/PD-L1 inhibitors in advanced melanoma and correlating the outcomes to PD-L1 levels. Results: After preclusion of ineligible studies, 11 studies were included. For PD-L1 >1% patients versus PD-L1 5% patients versus PD-L1 <5% patients, it was 2.22 (95% CI: 1.71–2.87; p < 0.00001). Conclusion: The current analysis indicates the value of PD-L1 positivity in predicting higher response from PD-1/PD-L1 agents. This molecular predictor – together with other predictors – may help further individualize treatment options for metastatic melanoma patients.
TL;DR: Although the means by which MSC home to sites of inflammation or tissue damage and exert their beneficial effects remain to be fully elucidated, they have recently been shown to adsorb a number of immunosuppressive and anticancer drugs that may further enhance their therapeutic potential.
Abstract: Mesenchymal stromal cells (MSC) are connective tissue progenitor cells with interesting immunoregulatory properties and are currently being assessed as cellular therapeutics in a variety of clinical applications. While bone marrow has been the traditional source, adipose tissue and umbilical cord are being used increasingly to generate MSC for therapeutic use as an allogeneic, off-the-shelf product. Although the means by which MSC home to sites of inflammation or tissue damage and exert their beneficial effects remain to be fully elucidated, they have recently been shown to adsorb a number of immunosuppressive and anticancer drugs that may further enhance their therapeutic potential.
TL;DR: A closer look is taken at the history and development of therapeutic targets to the PD-1/PD-ligand (L)1 pathway, clinical evidence, availability of biomarkers and their limitations in clinical practice and future strategies to improve treatment outcomes.
Abstract: Anti-programmed death (PD)-1 antibodies have now become the standard of care for advanced melanoma, with two drugs gaining US FDA approval in recent years: nivolumab and pembrolizumab. Both have demonstrated significant activity and durable response with a manageable toxicity profile. Despite initial success, ongoing challenges include patient selection and predictors of response, innate resistance and optimizing combination strategies. In this overview, we take a closer look at the history and development of therapeutic targets to the PD-1/PD-ligand (L)1 pathway, clinical evidence, availability of biomarkers and their limitations in clinical practice and future strategies to improve treatment outcomes.
TL;DR: The pathological features of a severe liver-injury associated with the administration of the anti-PD-1 agent nivolumab in a patient with glioblastoma are described for the first time.
Abstract: Immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies have dramatically changed the paradigm of cancer therapy over the past few years. The use of these agents is associated with a unique pattern of autoimmune-like/inflammatory side effects termed immune-related adverse events (irAEs), that may cause collateral damage to normal tissues. Although severe irAEs remain rare, they can become life-threatening if not anticipated and managed appropriately. Improving our knowledge of the mechanisms underlying the development of these toxicities is crucial to optimize clinical efficacy and safety of these new immunotherapeutics. Herein we describe for the first time the pathological features of a severe liver-injury associated with the administration of the anti-PD-1 agent nivolumab in a patient with glioblastoma.
TL;DR: Overall there was not any significant difference in overall survival and recurrence-free survival between patients undergoing specific immunotherapy and those in control group and most of the studies reported a positive outcome from treatment with specific Immunotherapy, although this was not significant.
Abstract: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Several approaches of active and passive immunotherapy for EOC have been studied. The aim of this systematic review was to assess the clinical efficacy of specific immunotherapy in patients with EOC. We found 4524 references in seven databases and we included ten controlled clinical trials with 2285 patients with EOC reporting five active immunotherapeutic agents and three passive immunotherapies. Meta-analysis of six studies showed that overall there was not any significant difference in overall survival and recurrence-free survival between patients undergoing specific immunotherapy and those in control group. Most of the studies we evaluated reported a positive outcome from treatment with specific immunotherapy, although this was not significant.