Journal Articles

Immunotherapy reviews

Reviews on preclinical or clinical cancer immunotherapy approaches

Cutaneous Adverse Events of Immune Checkpoint Inhibitors: A Summarized Overview

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BACKGROUND: The introduction of Immune Checkpoint Inhibitors in the recent years has resulted in high response rates and extended survival in patients with metastatic/advanced malignancies. Their mechanism of action is the indirect activation of cytotoxic T-cells through the blockade of inhibitory receptors of immunmodulatory pathways, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and its ligand (PD-L1). Despite their impressive therapeutic results, they can also induce immune-related toxicity, affecting various organs, including the skin. OBJECTIVE: To provide an updated summarized overview of the most common immune-mediated cutaneous side effects and their management. METHOD: English articles derived from the databases PubMed and SCOPUS and published between 2009 and 2018, were analyzed for this narrative review. RESULTS: The most common adverse cutaneous reactions include maculopapular rash, lichenoid reactions, vitiligo and pruritus, with severity Grade 1 or 2. Less frequent but eventually life threatening skin side effects, including Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms and Toxic Epidermal necrolysis, have also been reported. CONCLUSION: Basic knowledge of the Immune-Checkpoint-Inhibitors-induced skin toxicity is necessary in order to recognize these treatment-related complications. The most frequent skin side effects, such as maculopapular rash, vitiligo and pruritus, tend to subside under symptomatic treatment, so that permanent discontinuation of therapy is not commonly necessary. In the case of life threatening side effects, apart from the necessary symptomatic treatment, the immunotherapy should be permanently stopped. Information concerning the management of ICIs-mediated skin toxicity can be obtained from the literature as well as from the Summary of Product Characteristics of each agent.

Author Info: (1) Dermatology Department, University General Hospital of Patras. Greece. (2) Dermatology Department, University General Hospital of Patras. Greece. (3) Dermatology Department, University General Hospital of Patras. Greece.

Author Info: (1) Dermatology Department, University General Hospital of Patras. Greece. (2) Dermatology Department, University General Hospital of Patras. Greece. (3) Dermatology Department, University General Hospital of Patras. Greece.

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Combining vaccines and immune checkpoint inhibitors to prime, expand, and facilitate effective tumor immunotherapy

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INTRODUCTION: Multiple immune checkpoint inhibitors (ICIs) that modulate immune cells in the periphery and the tumor microenvironment (TME) have been approved, as have the therapeutic cancer vaccines sipuleucel-T for metastatic castration-resistant prostate cancer and talimogene laherparepvec (T-VEC) for metastatic melanoma. These developments provide rationale for combining these modalities in order to improve response rates and durability of responses in a variety of cancers. Preclinical data have shown that vaccines can induce immune responses that turn a tumor from "cold" to "hot," but vaccines do not appear to be highly active as monotherapy. Areas covered: Here we provide a review of the current state of vaccine and ICI combination studies. Expert commentary: Most combination trials are in early phases, but several are now in phase III. Vaccines that target antigens expressed exclusively on tumor cells, neoantigens, have the potential to induce robust antitumor responses. Several techniques for predicting which neoepitopes to target, based on tumor mutational profiling, are in various stages of development. In order to be successful, combination immunotherapy approaches must seek to prime the immune system, expand the immune response, and facilitate immune function within the TME.

Author Info: (1) a Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , MD , USA. (2) a

Author Info: (1) a Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , MD , USA. (2) a Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , MD , USA. (3) a Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , MD , USA.

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CD4+ T cell help in cancer immunology and immunotherapy

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Borst et al. comprehensively review how CD4+ T cells enhance the cytotoxic T lymphocyte (CTL) antitumor response. Proper CD4+ T cell help leads to clonal expansion and differentiation of CTLs into effector and memory T cells, and increases the cytotoxicity of CTLs, resulting in enhanced antitumor response. Topics reviewed include types and spatiotemporal stages of dendritic cell involvement and the intricate interplay with T cells, co-presentation of CD4+ and CD8+ epitopes, T cell costimulatory ligands (CD40L) and receptors (CD28, CD27), and cytokine (IL-12, IL-15) and chemokine (XCL1) production.

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Borst et al. comprehensively review how CD4+ T cells enhance the cytotoxic T lymphocyte (CTL) antitumor response. Proper CD4+ T cell help leads to clonal expansion and differentiation of CTLs into effector and memory T cells, and increases the cytotoxicity of CTLs, resulting in enhanced antitumor response. Topics reviewed include types and spatiotemporal stages of dendritic cell involvement and the intricate interplay with T cells, co-presentation of CD4+ and CD8+ epitopes, T cell costimulatory ligands (CD40L) and receptors (CD28, CD27), and cytokine (IL-12, IL-15) and chemokine (XCL1) production.

Cancer immunotherapy aims to promote the activity of cytotoxic T lymphocytes (CTLs) within a tumour, assist the priming of tumour-specific CTLs in lymphoid organs and establish efficient and durable antitumour immunity. During priming, help signals are relayed from CD4(+) T cells to CD8(+) T cells by specific dendritic cells to optimize the magnitude and quality of the CTL response. In this Review, we highlight the cellular dynamics and membrane receptors that mediate CD4(+) T cell help and the molecular mechanisms of the enhanced antitumour activity of CTLs. We outline how deficient CD4(+) T cell help reduces the response of CTLs and how maximizing CD4(+) T cell help can improve outcomes in cancer immunotherapy strategies.

Author Info: (1) Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands. j.borst@nki.nl. (2) Division of Tumour Biology and Immunology, The Netherlands Cancer Institute

Author Info: (1) Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands. j.borst@nki.nl. (2) Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands. (3) Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands. (4) Leiden University Medical Center and ISA Pharmaceuticals, Leiden, Netherlands. (5) Institute for Systems Immunology, Wurzburg, Germany.

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Microneedle arrays for vaccine delivery: The possibilities, challenges and use of nanoparticles as a combinatorial approach for enhanced vaccine immunogenicity

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INTRODUCTION: Vaccination is undoubtedly one of the greatest breakthroughs of modern preventative medicine. Despite this, there remain problems surrounding delivery, efficacy and compliance. Thus, there is a pressing need to develop cost-effective vaccine delivery systems that could expand the use of vaccines, particularly within developing countries. Microneedle (MN) arrays, due to their ease of use, painlessness and ability to target skin antigen presenting cells, provide an attractive technological platform for improved vaccine delivery and efficacy. Studies have demonstrated enhanced immunogenicity with the use of MN in comparison to that of the conventional needle. More recently, dissolving MN have been used for efficient delivery of nanoparticles (NP), as a means to enhance antigen immunogenicity. AREAS COVERED: This review introduces the fields of MN technology and nanotechnology and highlights the recent advances which have been made combining these two technologies for enhanced vaccine delivery and efficacy. Some of the key questions that remain to be addressed for adoption of MN in a clinical setting are also evaluated. EXPERT OPINION: MN-mediated vaccine delivery holds potential for expanding access to vaccines, with individuals in developing countries likely to be the principal beneficiaries. The combinatorial approach of utilising MN coupled with NP, provides the opportunity to enhance the immunogenicity of vaccine antigens.

Author Info: (1) a School of Pharmacy, Medical Biology Centre, Queens University Belfast , 97 Lisburn Road, Belfast BT9 7BL , United Kingdom . (2) a School

Author Info: (1) a School of Pharmacy, Medical Biology Centre, Queens University Belfast , 97 Lisburn Road, Belfast BT9 7BL , United Kingdom . (2) a School of Pharmacy, Medical Biology Centre, Queens University Belfast , 97 Lisburn Road, Belfast BT9 7BL , United Kingdom . (3) b Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University Belfast , United Kingdom . (4) a School of Pharmacy, Medical Biology Centre, Queens University Belfast , 97 Lisburn Road, Belfast BT9 7BL , United Kingdom .

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Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy

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Considerable interest surrounds the use of immune-checkpoint inhibitors in patients with solid tumours following the demonstration of the impressive clinical efficacy of anti-programmed cell death protein 1 and anti-programmed cell death 1 ligand 1 antibodies in several tumour types. However, the emergence of unexpected tumour response patterns, such as pseudoprogression or hyperprogression, might complicate the management of patients receiving these agents. Analysis of circulating tumour DNA (ctDNA) has been shown to have prognostic value by enabling the detection of residual proliferating disease in the adjuvant setting and estimation of tumour burden in the metastatic setting, which are key stratification biomarkers for use of immune-checkpoint inhibition (ICI). Furthermore, examinations of ctDNA for genetic predictors of responsiveness to immunotherapy, such as mutations, tumour mutational load, and microsatellite instability provide a noninvasive surrogate for tumour biopsy sampling. Proof-of-concept reports have also demonstrated that quantitative changes in ctDNA levels early in the course of disease are a promising tool for the assessment of responsiveness to ICI that might complement standard imaging approaches. Other applications of this technology are also currently under investigation, such as early detection of resistance to immunotherapy and characterization of mechanisms of resistance. The aim of this Review is to summarize available data on the application of ctDNA in patients receiving immunotherapy and to discuss the most promising future directions.

Author Info: (1) Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France. Versailles Saint Quentin en Yvelines University, Paris Saclay University, Saint Cloud, Paris, France

Author Info: (1) Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France. Versailles Saint Quentin en Yvelines University, Paris Saclay University, Saint Cloud, Paris, France. Circulating Tumor Biomarkers Laboratory, Institut Curie, PSL Research University, Paris, France. (2) Circulating Tumor Biomarkers Laboratory, Institut Curie, PSL Research University, Paris, France. (3) Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France. INSERM U932, Institut Curie, PSL Research University, Paris, France. (4) Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France. (5) INSERM U932, Institut Curie, PSL Research University, Paris, France. (6) INSERM U830, Institut Curie, PSL Research University, Paris, France. (7) Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France. Paris Descartes University, Paris, France. (8) Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France. fcbidard@curie.fr. Versailles Saint Quentin en Yvelines University, Paris Saclay University, Saint Cloud, Paris, France. fcbidard@curie.fr. Circulating Tumor Biomarkers Laboratory, Institut Curie, PSL Research University, Paris, France. fcbidard@curie.fr.

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Plasmacytoid dendritic cell in immunity and cancer

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Plasmacytoid dendritic cells (pDCs) comprise a subset of dendritic cells characterized by their ability to produce large amount of type I interferon (IFN-I/alpha). Originally recognized for their role in modulating immune responses to viral stimulation, growing interest has been directed toward their contribution to tumorigenesis. Under normal conditions, Toll-like receptor (TLR)-activated pDCs exhibit robust IFN-alpha production and promote both innate and adaptive immune responses. In cancer, however, pDCs demonstrate an impaired response to TLR7/9 activation, decreased or absent IFN-alpha production and contribute to the establishment of an immunosuppressive tumor microenvironment. In addition to IFN-alpha production, pDCs can also act as antigen presenting cells (APCs) and regulate immune responses to various antigens. The significant role played by pDCs in regulating both the innate and adaptive components of the immune system makes them a critical player in cancer immunology. In this review, we discuss the development and function of pDCs as well as their role in innate and adaptive immunity. Finally, we summarize pDC contribution to cancer pathogenesis, with a special focus on primary malignant brain tumor, their significance in the era of immunotherapy and suggest potential strategies for pDC-targeted therapy.

Author Info: (1) Department of Neurosurgery, IU Simon Cancer Center, Indiana University, Indiana, USA. (2) Department of Neurosurgery, IU Simon Cancer Center, Indiana University, Indiana, USA. (3)

Author Info: (1) Department of Neurosurgery, IU Simon Cancer Center, Indiana University, Indiana, USA. (2) Department of Neurosurgery, IU Simon Cancer Center, Indiana University, Indiana, USA. (3) Department of Neurosurgery, IU Simon Cancer Center, Indiana University, Indiana, USA. Electronic address: mdey@iu.edu.

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Interleukin-1 Beta-A Friend or Foe in Malignancies

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Interleukin-1 beta (IL-1beta) is induced by inflammatory signals in a broad number of immune cell types. IL-1beta (and IL-18) are the only cytokines which are processed by caspase-1 after inflammasome-mediated activation. This review aims to summarize current knowledge about parameters of regulation of IL-1beta expression and its multi-facetted role in pathophysiological conditions. IL-1 signaling activates innate immune cells including antigen presenting cells, and drives polarization of CD4+ T cells towards T helper type (Th) 1 and Th17 cells. Therefore, IL-1beta has been attributed a largely beneficial role in resolving acute inflammations, and by initiating adaptive anti-tumor responses. However, IL-1beta generated in the course of chronic inflammation supports tumor development. Furthermore, IL-1beta generated within the tumor microenvironment predominantly by tumor-infiltrating macrophages promotes tumor growth and metastasis via different mechanisms. These include the expression of IL-1 targets which promote neoangiogenesis and of soluble mediators in cancer-associated fibroblasts that evoke antiapoptotic signaling in tumor cells. Moreover, IL-1 promotes the propagation of myeloid-derived suppressor cells. Using genetic mouse models as well as agents for pharmacological inhibition of IL-1 signaling therapeutically applied for treatment of IL-1 associated autoimmune diseases indicate that IL-1beta is a driver of tumor induction and development.

Author Info: (1) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Rebekka.Bent@unimedizin-mainz.de. (2) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Lorna.Moll@unimedizin-mainz.de. (3) Department of

Author Info: (1) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Rebekka.Bent@unimedizin-mainz.de. (2) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Lorna.Moll@unimedizin-mainz.de. (3) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. Stephan.Grabbe@unimedizin-mainz.de. (4) Department of Dermatology, University Medical Center, 55131 Mainz, Germany. mbros@uni-mainz.de.

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New PDL1 inhibitors for non-small cell lung cancer: focus on pembrolizumab

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The advent of immune-checkpoint inhibitors during the past decade represents a major advancement in the treatment of non-small cell lung cancer (NSCLC) with personalized treatment. Platinum-based chemotherapy has reached its efficacy threshold, with its use remaining limited by its toxicity. For NSCLC, inhibitors of the PD1 protein and its ligand PDL1 show promising clinical activity and induce durable responses in patients with advanced disease. The US Food and Drug Administration has approved pembrolizumab for treatment-naive metastatic NSCLC with >/=50% of tumor cells expressing PDL1 and for metastatic NSCLC with >/=1% PDL1 expression after progression following first-line platinum-based doublet chemotherapy. In 2017, it also authorized the first-line combination of pembrolizumab and carboplatin-pemetrexed chemotherapy without selection based on PDL1 expression, but European health authorities are still waiting for the results of a Phase III trial. In this review, the clinical results of published and ongoing studies evaluating pembrolizumab for advanced NSCLC are analyzed and the potential role of PDL1 as a factor predictive of overall responses addressed.

Author Info: (1) Pneumology Department, Hopital d'Instruction des Armees Percy, Paris, bylicki.olivier@yahoo.fr. (2) Respiratory Department, Hopital d'Instruction des Armees Saint-Anne, Toulon. (3) Pneumology Department, CHI Creteil, Paris

Author Info: (1) Pneumology Department, Hopital d'Instruction des Armees Percy, Paris, bylicki.olivier@yahoo.fr. (2) Respiratory Department, Hopital d'Instruction des Armees Saint-Anne, Toulon. (3) Pneumology Department, CHI Creteil, Paris, France. (4) Pneumology Department, CHI Creteil, Paris, France.

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Listeria monocytogenes as a Vector for Cancer Immunotherapy: Current Understanding and Progress

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Listeria monocytogenes, a Gram-positive facultative anaerobic bacterium, is becoming a popular vector for cancer immunotherapy. Indeed, multiple vaccines have been developed utilizing modified Listeria as a tool for generating immune responses against a variety of cancers. Moreover, over a dozen clinical trials testing Listeria cancer vaccines are currently underway, which will help to understand the utility of Listeria vaccines in cancer immunotherapy. This review aims to summarize current views on how Listeria-based vaccines induce potent antitumor immunity and the current state of Listeria-based cancer vaccines in clinical trials.

Author Info: (1) Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA. John.Flickinger@jefferson.edu. (2) Department of Dermatology, Thomas Jefferson University

Author Info: (1) Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA. John.Flickinger@jefferson.edu. (2) Department of Dermatology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA. Ulrich.Rodeck@jefferson.edu. (3) Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA. Adam.Snook@jefferson.edu.

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Boosting half-life and effector functions of therapeutic antibodies by Fc-engineering: An interaction-function review

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Due mainly to their high level of affinity and specificity, therapeutic monoclonal antibodies (mAbs) have been frequently selected as treatment for cancer, autoimmune or chronic inflammatory diseases. Despite the increasing number of mAbs and related products in the biopharmaceutical market, they are still expensive, can cause undesired side effects, and eventually cause resistance. Antibody engineering, which emerged to overcome limitations faced by mAb therapy, has supported the development of modified mAbs for immunotherapy. As part of this approach, researchers have invested in obtaining antibody fragments, as well as in Fc region modifications, since interactions with Fc receptors influence an antibody's half-life and mechanism of action. Thus, Fc engineering results in antibodies with more desirable characteristics and functions for which they are intended, creating "fit-for-purpose" antibodies with reduced side effects. Furthermore, aglycosylated antibodies, produced in bacterial cultivation, have been an alternative to create new effector functional human immunotherapeutics, while reducing mAb therapy costs. This review highlights some features that enhance mAb performance, related to the improvement of antibody half-life and effector responses by both Fc-engineering and glycoengineering.

Author Info: (1) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. Electronic address: marcela.gambim@fiocruz.br. (2) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. (3) Fundacao

Author Info: (1) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. Electronic address: marcela.gambim@fiocruz.br. (2) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. (3) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. (4) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. (5) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil.

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