scholarly journals Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2021-217260
Author(s):  
Tommaso Morelli ◽  
Kohei Fujita ◽  
Gil Redelman-Sidi ◽  
Paul T Elkington
Keyword(s):  
Immune Response ◽  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immunosuppressive Treatment ◽  
Common Side Effect ◽  
Inflammatory Immune Response ◽  
New Framework

Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment. However, immune-related adverse events (irAEs) are a common side effect which can mimic infection. Additionally, treatment of irAEs with corticosteroids and other immunosuppressant agents can lead to opportunistic infection, which we have classed as immunotherapy infections due to immunosuppression. However, emerging reports demonstrate that some infections can be precipitated by ICIs in the absence of immunosuppressive treatment, in contrast to the majority of reported cases. These infections are characterised by a dysregulated inflammatory immune response, and so we propose they are described as immunotherapy infections due to dysregulated immunity. This review summarises the rapidly emerging evidence of these phenomena and proposes a new framework for considering infection in the context of cancer immunotherapy.

scholarly journals Treatment of rheumatic immune-related adverse events due to cancer immunotherapy with immune checkpoint inhibitors—is it time for a paradigm shift?

2020 ◽  
Author(s):  
Katerina Chatzidionysiou ◽  
Matina Liapi ◽  
Georgios Tsakonas ◽  
Iva Gunnarsson ◽  
Anca Catrina
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Potential Risk ◽  
Immune Checkpoint ◽  
Paradigm Shift ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Current Evidence ◽  
Inadequate Response ◽  
High Efficacy

Abstract Immunotherapy has revolutionized cancer treatment during the last years. Several monoclonal antibodies that are specific for regulatory checkpoint molecules, that is, immune checkpoint inhibitors (ICIs), have been approved and are currently in use for various types of cancer in different lines of treatment. Cancer immunotherapy aims for enhancing the immune response against cancer cells. Despite their high efficacy, ICIs are associated to a new spectrum of adverse events of autoimmune origin, often referred to as immune-related adverse events (irAEs), which limit the utility of these drugs. These irAEs are quite common and can affect almost every organ. The grade of toxicity varies from very mild to life-threatening. The pathophysiological mechanisms behind these events are not fully understood. In this review, we will summarize current evidence specifically regarding the rheumatic irAEs and we will focus on current and future treatment strategies. Treatment guidelines largely support the use of glucocorticoids as first-line therapy, when symptomatic therapy is not efficient, and for more persistent and/or moderate/severe degree of inflammation. Targeted therapies are higher up in the treatment pyramid, after inadequate response to glucocorticoids and conventional, broad immunosuppressive agents, and for severe forms of irAEs. However, preclinical data provide evidence that raise concerns regarding the potential risk of impaired antitumoral effect. This potential risk of glucocorticoids, together with the high efficacy and potential synergistic effect of newer, targeted immunomodulation, such as tumor necrosis factor and interleukin-6 blockade, could support a paradigm shift, where more targeted treatments are considered earlier in the treatment sequence.

scholarly journals Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors

Rheumatology ◽  
2019 ◽  
Vol 58 (Supplement_7) ◽  
pp. vii59-vii67 ◽  
Author(s):  
Sophia C Weinmann ◽  
David S Pisetsky
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immunosuppressive Treatment ◽  
Cell Repertoire ◽  
Autoantibody Production ◽  
Rheumatic Manifestations ◽  
Checkpoint Inhibitor Therapy

AbstractImmune checkpoint inhibitors are novel biologic agents to treat cancer by inhibiting the regulatory interactions that limit T cell cytotoxicity to tumours. Current agents target either CTLA-4 or the PD-1/PD-L1 axis. Because checkpoints may also regulate autoreactivity, immune checkpoint inhibitor therapy is complicated by side effects known as immune-related adverse events (irAEs). The aim of this article is to review the mechanisms of these events. irAEs can involve different tissues and include arthritis and other rheumatic manifestations. The frequency of irAEs is related to the checkpoint inhibited, with the combination of agents more toxic. Because of their severity, irAEs can limit therapy and require immunosuppressive treatment. The mechanisms leading to irAEs are likely similar to those promoting anti-tumour responses and involve expansion of the T cell repertoire; furthermore, immune checkpoint inhibitors can affect B cell responses and induce autoantibody production. Better understanding of the mechanisms of irAEs will be important to improve patient outcome as well as quality of life during treatment.

scholarly journals Pulmonary adverse events due to immune checkpoint inhibitors: A literature review

2021 ◽  
Author(s):  
Vasiliki Epameinondas Georgakopoulou ◽  
Nikolaos Garmpis ◽  
Dimitrios Mermigkis ◽  
Christos Damaskos ◽  
Serafeim Chlapoutakis ◽  
...  
Keyword(s):  
Immune System ◽  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Pulmonary Nodules ◽  
Airway Disease

Cancer immunotherapy aims to stimulate the immune system to fight against tumors, utilizing the presentation of molecules on the surface of the malignant cells that can be recognized by the antibodies of the immune system. Immune checkpoint inhibitors, a type of cancer immunotherapy, are broadly used in different types of cancer, improving patients’ survival and quality of life. However, treatment with these agents causes immune-related toxicities affecting many organs. The most frequent pulmonary adverse event is pneumonitis representing a non-infective inflammation localized to the interstitium and alveoli. Other lung toxicities include airway disease, pulmonary vasculitis, sarcoid-like reactions, infections, pleural effusions, pulmonary nodules, diaphragm myositis and allergic bronchopulmonary aspergillosis. This review aims to summarize these pulmonary adverse events, underlining the significance of an optimal expeditious diagnosis and management.   

An innovative combined immunization platform for personalized cancer immunotherapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14225-e14225
Author(s):  
Jessica Matta ◽  
Célia Matta ◽  
Emilie Thiebault Peter ◽  
David Moulaert ◽  
Robert Drillien ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Vector Coding ◽  
Melanoma Model ◽  
Dna Vector ◽  
Personalized Cancer

e14225 Background: Activity of immune checkpoint inhibitors relies mainly on the presence of an immune response directed against neoantigens resulting from tumor specific mutations. The induction and/or amplification of such an immune response is expected to increase the activity of these therapies. We describe here a novel immunization platform developed for the purpose of personalized cancer immunotherapy. This platform integrates a DNA vector coding for neoantigens, a live modified vaccinia of strain Ankara (MVA) used as a physiologic adjuvant and anti-CTLA-4 as a locally acting early immune checkpoint blocker. Methods: Immune potency was assessed in C57BL6 mice injected subcutaneously three times five days apart with an ovalbumine (OVA) expressing DNA vector (100 µg), either alone or in combination with increasing doses of MVA (up to 2.5x107 plaque forming units, pfu) and increasing doses of anti-CTLA-4 (up to 100 µg). OVA specific immune responses were measured by ELISpot. Anti-tumor efficacy was then investigated with a similar administration scheme in a therapeutic B16F10 mice melanoma model with a DNA vector coding for the B16F10-M30 tumor neoantigen. Results: At an optimal dose of 2.5x106 pfu, MVA significantly improved OVA specific immune response up to 10 times higher as compared to vector alone. Addition of CTLA-4 blockade further increased the magnitude of response, up to 30 times higher than with vector alone. Both MVA and CTLA-4 demonstrated a bell-shaped dose dependent effect. In tumor-bearing animals, 80% experienced durable tumor-free survival when treated with the combination therapy as compared to less than 20% in untreated animals or animals treated with each component independently. Treatment appeared feasible and well-tolerated. Conclusions: Neoantigen coding DNA vector, MVA and CTLA-4 immune checkpoint blockade, when co-administered in immunocompetent C57BL6 mice, acted synergistically to induce a cellular immune response. The same approach translated into a strong anti-tumoral response in an aggressive melanoma model. This combined immunization platform appears as a potential novel way to enhance clinical benefit from current immune checkpoint inhibitors.

scholarly journals Unleashing the tiger – iatrogenic autoimmunity from cancer immunotherapy drugs

JRSM Open ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 205427041774690 ◽  
Author(s):  
Queenie Luu ◽  
Gabor Major
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Organ Specific

Immune checkpoint inhibitors can lead to the development of organ and non-organ specific immune related adverse events.

scholarly journals The Price of Success: Immune-Related Adverse Events from Immunotherapy in Lung Cancer

2021 ◽  
Vol 28 (6) ◽  
pp. 4392-4407
Author(s):  
Courtney H. Coschi ◽  
Rosalyn A. Juergens
Keyword(s):  
Immune Response ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Low Grade ◽  
Cancer Type ◽  
Immune System Activation ◽  
Cancer Types ◽  
System Activation

Cancer immunotherapy has the goal of enhancing a patient’s intrinsic immune processes in order to mount a successful immune response against tumor cells. Cancer cells actively employ tactics to evade, delay, alter, or attenuate the anti-tumor immune response. Immune checkpoint inhibitors (ICIs) modulate endogenous regulatory immune mechanisms to enhance immune system activation, and have become the mainstay of therapy in many cancer types. This activation occurs broadly and as a result, activation is supraphysiologic and relatively non-specific, which can lead to immune-related adverse events (irAEs), the frequency of which depends on the patient, the cancer type, and the specific ICI antibody. Careful assessment of patients for irAEs through history taking, physical exam, and routine laboratory assessments are key to identifying irAEs at early stages, when they can potentially be managed more easily and before progressing to higher grades or more serious effects. Generally, most patients with low grade irAEs are eligible for re-challenge with ICIs, and the use of corticosteroids to address an irAE is not associated with poorer patient outcomes. This paper reviews immune checkpoint inhibitors (ICIs) including their mechanisms of action, usage, associated irAEs, and their management.

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