scholarly journals Applications of Magnetite Nanoparticles in Cancer Immunotherapies: Present Hallmarks and Future Perspectives

2021 ◽  
Vol 12 ◽  
Author(s):  
Qingle Song ◽  
Amaneh Javid ◽  
Guofang Zhang ◽  
Yang Li
Keyword(s):  
Side Effects ◽  
Magnetite Nanoparticles ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Tumor Immune Evasion ◽  
Therapeutic Benefits ◽  
Tumor Killing ◽  
Cancer Immunotherapeutic

Current immuno-oncotherapeutic protocols that inhibit tumor immune evasion have demonstrated great clinical success. However, the therapeutic response is limited only to a percentage of patients, and the immune-related adverse events can compromise the therapeutic benefits. Therefore, improving cancer immunotherapeutic approaches that pursue high tumor suppression efficiency and low side effects turn out to be a clinical priority. Novel magnetite nanoparticles (MNPs) exhibit great potential for therapeutic and imaging applications by utilizing their properties of superparamagnetism, good biocompatibility, as well as the easy synthesis and modulation/functionalization. In particular, the MNPs can exert magnetic hyperthermia to induce immunogenic cell death of tumor cells for effective antigen release and presentation, and meanwhile polarize tumor-associated macrophages (TAMs) to M1 phenotype for improved tumor killing capability, thus enhancing the anti-tumor immune effects. Furthermore, immune checkpoint antibodies, immune-stimulating agents, or tumor-targeting agents can be decorated on MNPs, thereby improving their selectivity for the tumor or immune cells by the unique magnetic navigation capability of MNPs to promote the tumor killing immune therapeutics with fewer side effects. This mini-review summarizes the recent progress in MNP-based immuno-oncotherapies, including activation of macrophage, promotion of cytotoxic T lymphocyte (CTL) infiltration within tumors and modulation of immune checkpoint blockade, thus further supporting the applications of MNPs in clinical therapeutic protocols.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

scholarly journals O4 Mechanisms of lung cancer hyper-progression promoted by PD-1 immune checkpoint blockade

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A5.1-A5
Author(s):  
A Martinez-Usatorre ◽  
E Kadioglu ◽  
C Cianciaruso ◽  
B Torchia ◽  
J Faget ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Checkpoint Blockade ◽  
Therapeutic Benefits ◽  
Angiopoietin 2

BackgroundImmune checkpoint blockade (ICB) with antibodies against PD-1 or PD-L1 may provide therapeutic benefits in patients with non-small cell lung cancer (NSCLC). However, most tumours are resistant and cases of disease hyper-progression have also been reported.Materials and MethodsGenetically engineered mouse models of KrasG12Dp53null NSCLC were treated with cisplatin along with antibodies against angiopoietin-2/VEGFA, PD-1 and CSF1R. Tumour growth was monitored by micro-computed tomography and the tumour vasculature and immune cell infiltrates were assessed by immunofluorescence staining and flow cytometry.ResultsCombined angiopoietin-2/VEGFA blockade by a bispecific antibody (A2V) modulated the vasculature and abated immunosuppressive macrophages while increasing CD8+effector T cells in the tumours, achieving disease stabilization comparable or superior to cisplatin-based chemotherapy. However, these immunological responses were unexpectedly limited by the addition of a PD-1 antibody, which paradoxically enhanced progression of a fraction of the tumours through a mechanism involving regulatory T cells and macrophages. Elimination of tumour-associated macrophages with a CSF1R-blocking antibody induced NSCLC regression in combination with PD-1 blockade and cisplatin.ConclusionsThe immune cell composition of the tumour determines the outcome of PD-1 blockade. In NSCLC, high infiltration of regulatory T cells and immunosuppressive macrophages may account for tumour hyper-progression upon ICB.Disclosure InformationA. Martinez-Usatorre: None. E. Kadioglu: None. C. Cianciaruso: None. B. Torchia: None. J. Faget: None. E. Meylan: None. M. Schmittnaegel: None. I. Keklikoglou: None. M. De Palma: None.

scholarly journals Therapeutic Implications of Tumor Microenvironment in Lung Cancer: Focus on Immune Checkpoint Blockade

2022 ◽  
Vol 12 ◽  
Author(s):  
Carlo Genova ◽  
Chiara Dellepiane ◽  
Paolo Carrega ◽  
Sara Sommariva ◽  
Guido Ferlazzo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Regulatory Elements ◽  
Immune Checkpoint Blockade ◽  
Therapeutic Implications ◽  
Investigational Agents

In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of “classic” ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy.

scholarly journals Immune checkpoint blockade in the treatment of malignant tumor: current statue and future strategies

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wenwen Yang ◽  
Caining Lei ◽  
Shaoming Song ◽  
Wutang Jing ◽  
Chuanwei Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Malignant Tumor ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Response ◽  
Inhibitory Molecule

AbstractAfter being stagnant for decades, there has finally been a paradigm shift in the treatment of cancer with the emergence and application of immune checkpoint inhibitors (ICIs). The most extensively utilized ICIs are targeting the pathways involving programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). PD-1, as an crucial immune inhibitory molecule, by and large reasons the immune checkpoint response of T cells, making tumor cells get away from immune surveillance. Programmed cell death ligand-1 (PD-L1) is exceptionally expressed in most cancers cells and approves non-stop activation of the PD-1 pathway in the tumor microenvironment. PD-1/PD-L1 inhibitors can block the combination of PD-1 and PD-L1, inhibit hostile to regulatory signals, and restore the activity of T cells, thereby bettering immune response. The current researchers assume that the efficacy of these drugs is related to PD-L1 expression in tumor tissue, tumor mutation burden (TMB), and other emerging biomarkers. Although malignant tumors can benefit from the immunotherapy of PD-1/PD-L1 inhibitors, formulating a customized medication model and discovering biomarkers that can predict efficacy are the new trend in the new era of malignant tumor immunotherapy. This review summarizes the mechanism of action of PD-1/PD-L1 inhibitors, their clinical outcomes on various malignant tumors, their efficacy biomarkers, as well as predictive markers of irAEs.

scholarly journals Management of side effects of immune checkpoint blockade by anti-CTLA-4 and anti-PD-1 antibodies in metastatic melanoma

2016 ◽  
Vol 14 (7) ◽  
pp. 662-681 ◽  
Author(s):  
Katharina C. Kähler ◽  
Jessica C. Hassel ◽  
Lucie Heinzerling ◽  
Carmen Loquai ◽  
Rotraut Mössner ◽  
...  
Keyword(s):  
Side Effects ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Immunotherapy Associated Pulmonary Toxicity: Biology Behind Clinical and Radiological Features

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 305 ◽  
Author(s):  
Michele Porcu ◽  
Pushpamali De Silva ◽  
Cinzia Solinas ◽  
Angelo Battaglia ◽  
Marina Schena ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Immune Checkpoint ◽  
Pulmonary Toxicity ◽  
Clinical Symptoms ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Multidisciplinary Teams ◽  
Programmed Cell Death 1 ◽  
Radiological Patterns

The broader use of immune checkpoint blockade in clinical routine challenges clinicians in the diagnosis and management of side effects which are caused by inflammation generated by the activation of the immune response. Nearly all organs can be affected by immune-related toxicities. However, the most frequently reported are: fatigue, rash, pruritus, diarrhea, nausea/vomiting, arthralgia, decreased appetite and abdominal pain. Although these adverse events are usually mild, reversible and not frequent, an early diagnosis is crucial. Immune-related pulmonary toxicity was most frequently observed in trials of lung cancer and of melanoma patients treated with the combination of the anti-cytotoxic T lymphocyte antigen (CTLA)-4 and the anti-programmed cell death-1 (PD-1) antibodies. The most frequent immune-related adverse event in the lung is represented by pneumonitis due to the development of infiltrates in the interstitium and in the alveoli. Clinical symptoms and radiological patterns are the key elements to be considered for an early diagnosis, rendering the differential diagnosis crucial. Diagnosis of immune-related pneumonitis may imply the temporary or definitive suspension of immunotherapy, along with the start of immuno-suppressive treatments. The aim of this work is to summarize the biological bases, clinical and radiological findings of lung toxicity under immune checkpoint blockade, underlining the importance of multidisciplinary teams for an optimal early diagnosis of this side effect, with the aim to reach an improved patient care.

scholarly journals Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution

2014 ◽  
Vol 21 (2) ◽  
pp. 371-381 ◽  
Author(s):  
Mabel Ryder ◽  
Margaret Callahan ◽  
Michael A Postow ◽  
Jedd Wolchok ◽  
James A Fagin
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Hormone Replacement ◽  
Symptomatic Relief ◽  
Hormone Secretion ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Increased Risk

Novel immune checkpoint blockade with ipilimumab, an antibody blocking the cytotoxic T-lymphocyte antigen 4 (CTLA4), is revolutionizing cancer therapy. However, ipilimumab induces symptomatic, sometimes severe, endocrine immune-related adverse events (irAEs) that are inconsistently recognized and reported. The objective of this review was to comprehensively characterize the incidence, presentation, and management of endocrinopathies following ipilimumab therapy in a single center that is highly specialized in immune checkpoint blockade. We carried out a retrospective analysis of endocrine irAEs in melanoma patients receiving ipilimumab therapy in clinical trials between 2007 and 2013. A total of 256 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as radiographic studies and the clinical histories of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Following ipilimumab therapy, the overall incidence of hypophysitis was 8% and that of hypothyroidism/thyroiditis 6%. Primary adrenal dysfunction was rare. Therapy with a combination of ipilimumab and nivolumab, an anti-programmed cell death 1 (PDCD1, also called PD1) receptor antibody, was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis. Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion rarely recovered. In summary, we observed that CTLA4 blockade alone, and in particular in combination with PD1 blockade, is associated with an increased risk of symptomatic, sometimes severe, hypophysitis as well as thyroid dysfunction. Prompt initiation with hormone replacement reverses symptoms. Evaluation and reporting of endocrine irAEs in clinical trials should be done using standardized diagnostic criteria and terminology.

scholarly journals Combinatorial Approach to Improve Cancer Immunotherapy: Rational Drug Design Strategy to Simultaneously Hit Multiple Targets to Kill Tumor Cells and to Activate the Immune System

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Shweta Joshi ◽  
Donald L. Durden
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Rational Drug Design ◽  
Therapeutic Interventions ◽  
Epigenetic Therapy ◽  
T Cell Therapy

Cancer immunotherapy, including immune checkpoint blockade and adoptive CAR T-cell therapy, has clearly established itself as an important modality to treat melanoma and other malignancies. Despite the tremendous clinical success of immunotherapy over other cancer treatments, this approach has shown substantial benefit to only some of the patients while the rest of the patients have not responded due to immune evasion. In recent years, a combination of cancer immunotherapy together with existing anticancer treatments has gained significant attention and has been extensively investigated in preclinical or clinical studies. In this review, we discuss the therapeutic potential of novel regimens combining immune checkpoint inhibitors with therapeutic interventions that (1) increase tumor immunogenicity such as chemotherapy, radiotherapy, and epigenetic therapy; (2) reverse tumor immunosuppression such as TAMs, MDSCs, and Tregs targeted therapy; and (3) reduce tumor burden and increase the immune effector response with rationally designed dual or triple inhibitory chemotypes.

Practical Management of Immune-Related Adverse Events from Immune Checkpoint Protein Antibodies for the Oncologist

2012 ◽  
pp. 174-177 ◽  
Author(s):  
Jeffrey S. Weber
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Early Recognition ◽  
Cell Cancer ◽  
Immune Checkpoint Blockade ◽  
Physician Education ◽  
Programmed Death 1 ◽  
Grade 3 ◽  
Immune Checkpoint Proteins

Overview: Monoclonal antibodies directed against immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1), can boost endogenous immune responses directed against tumor cells. Recently, ipilimumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma, and the anti-PD-1 antibody BMS-936558 has shown promising results in patients with melanoma, non-small cell lung cancer, and renal cell cancer. During treatment with these antibodies, a unique set of toxicities occur called immune-related adverse events (irAEs). These irAEs may occur at any time during treatment and include colitis characterized by a mild to moderate but occasionally severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab, and a subset of those side effects has also been observed with BMS-936558. Patient and physician education as well as good patient–caretaker communication are keys to limiting the morbidity of irAEs. Early recognition of these irAEs and initiation of treatment are critical to reduce the risk of complications, since virtually all irAEs are reversible with the use of steroids and other immune suppressants. The onset of grade 3 to 4 irAEs correlated with treatment response in some ipilimumab studies. This article provides detailed description and recommendations for practicing oncologists to manage the common irAEs associated with antibodies against immune checkpoint blockade.

scholarly journals A Highlight of the Mechanisms of Immune Checkpoint Blocker Resistance

2020 ◽  
Vol 8 ◽  
Author(s):  
Qian Huang ◽  
Yanna Lei ◽  
Xiaoying Li ◽  
Fukun Guo ◽  
Ming Liu
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Acquired Resistance ◽  
Cancer Control ◽  
Immune Checkpoint Blockade ◽  
Tumor Resistance ◽  
Extrinsic Factors ◽  
Tumor Immune Evasion ◽  
Immune Checkpoint Blockers

In recent years, as our understanding of tumor immunology is continuously improved, immunotherapy has come to the center stage of cancer therapy and is deemed as the most promising approach for cancer control. Although immunotherapy, particularly immune checkpoint blockade (ICB), has achieved a milestone in several types of tumors, the majority of cancer patients do not benefit from immunotherapy. The dismal outcome of cancer immunotherapy is mainly due to primary or acquired resistance arising from tumor immune evasion. Exploring the mechanisms of tumor immune evasion in the course of immunotherapy may identify biological targets to conquer tumor resistance to immunotherapy. In this review, we highlight tumor cell-intrinsic and -extrinsic factors that may underlie tumor resistance to immune checkpoint blockers. Targeting these factors in combination with immune checkpoint blockers points to the future direction of cancer immunotherapy.

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