Expression of Immune Checkpoint Regulators, Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) and CD137 in Cervical Carcinomas

2021 ◽  
Author(s):  
Ari Kassardjian ◽  
Neda Moatamed
Keyword(s):  
T Lymphocyte ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Staining Reaction ◽  
Costimulatory Receptor ◽  
Fda Approval ◽  
Cervical Cancer Cells ◽  
Significant Expression

Abstract Introduction: Immune checkpoint inhibitors in cancer therapy has a significant role in oncology. One of these immune checkpoint mediators is cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Inhibition of the CTLA-4 pathway has already led to the FDA approval of Ipilimumab (anti-CTLA-4), a targeted therapy for melanoma and other malignancies. CD137 is an inducible, costimulatory receptor of the tissue necrosis factor receptor superfamily expressed on activated immune cells. Clinical trials had also been set for anti-CD137 in several malignancies. We investigated the expression of CTLA-4 and CD137 antibodies in benign and malignant uterine cervical tissues. Method: We assessed CTLA-4 and CD137 expression on a tissue microarray (TMA) comprising of 100 normal, non-neoplastic, and neoplastic cervical tissues. When detected as strong granular cytoplasmic reaction in the epithelial cells, CTLA-4 expression was scored as positive. For CD137, the results were recorded based on the presence or absence of staining reaction on the cell membranes of the lymphoplasmacytic infiltrate. Result: Overall, CTLA-4 was positive in 30% (30/100) of the cervical malignancies. Subcategorically, 20% of invasive endocervical adenocarcinomas, 62.5% of adenosquamous carcinomas, and 31% of squamous cell carcinomas were positive for CTLA-4 with a tendency toward lower grades SCCs. CD137 was positive in lymphoplasmacytic infiltrates of all endocervical adenocarcinomas, 90.5% of squamous cell carcinoma, and 87.5% cores of adenosquamous carcinomas. Conclusion: This study has found a significant expression of CTLA-4 in cervical cancer cells and CD137 positivity of lymphoplasmacytic infiltrates with potentials for future targeted immunotherapy.

scholarly journals Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease

2020 ◽  
Vol 38 (6) ◽  
pp. 576-583 ◽  
Author(s):  
Hamzah Abu-Sbeih ◽  
David M. Faleck ◽  
Biagio Ricciuti ◽  
Robin B. Mendelsohn ◽  
Abdul R. Naqash ◽  
...  
Keyword(s):  
Adverse Events ◽  
T Lymphocyte ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Inhibitor Therapy ◽  
Checkpoint Inhibitor Therapy ◽  
Inflammatory Bowel

PURPOSE The risk of immune checkpoint inhibitor therapy–related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors. PATIENTS AND METHODS We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events. RESULTS Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn’s disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event–related deaths were recorded. Anti–cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively). CONCLUSION Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.

scholarly journals Toxicidade Cutânea dos Inibidores de Checkpoint Imunológico: Uma Revisão Narrativa

2020 ◽  
Vol 33 (5) ◽  
pp. 335
Author(s):  
Nuno Gomes ◽  
Vincent Sibaud ◽  
Filomena Azevedo ◽  
Sofia Magina
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Adverse Events ◽  
T Lymphocyte ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Cutaneous Toxicity ◽  
Cell Death Protein

Introduction: Immune checkpoint inhibitors revolutionized anti-neoplastic treatment. Recently, the European Medicines Agency and the United States Food and Drug Administration approved inhibitors of various immune checkpoints, namely the cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1 and its ligand. Despite the added benefits in the treatment of several neoplasms, immune checkpoint blockade may also be associated with multiple immune-related adverse events.Material and Methods: A literature review in PubMed database on the cutaneous toxicity of immune checkpoint inhibitors was performed until April 30, 2019.Results and Discussion: A total of 380 articles were initially screened, of which 75 are the basis of this bibliographic review. The immune checkpoint inhibitors monoclonal antibodies produce their beneficial effects by activating the patient’s immune system. This activation also results in adverse events that can affect any organ, whereas cutaneous toxicity is the most frequent and precocious. The adverse events of the programmed cell death protein 1 and its ligand and of the cytotoxic T-lymphocyte-associated protein 4 are similar (class effect), despite the apparent higher skin toxicity of inhibitors of the cytotoxic T-lymphocyte-associated protein 4 (or its use in combination with inhibitors of programmed cell death protein 1 and its ligand). The most common cutaneous toxicities are maculopapular exanthema and pruritus, but other more specific adverse effects (e.g. lichenoid or psoriasiform reaction, vitiligo, sarcoidosis, among others) or located in the oral mucosa and/or adnexa are underreported.Conclusion: Given the high rate of cutaneous toxicity associated with new immune checkpoint inhibitors and their impact on quality of life, their early recognition and appropriate approach are crucial in the treatment of cancer patients. Observation by a dermatologist should be provided in patients with certain toxicities.

scholarly journals Management of immune-related adverse events in patients treated with immune checkpoint inhibitors– Rheumatology point of view

2018 ◽  
Vol 18 (2) ◽  
pp. 56-60
Author(s):  
Cheuk Man Ho ◽  
Chi Chiu Mok
Keyword(s):  
Cell Death ◽  
Adverse Events ◽  
T Lymphocyte ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Standard Treatment ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Point Of View ◽  
Cell Death Protein

Abstract The development of immunotherapy has revolutionized the cancer treatment in the recent years. Immune checkpoint inhibitors (ICPis) such as anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death protein (anti-PD1) and its ligand (anti-PDL1) have become part of the standard treatment of various malignancies. Immune-related adverse events (irAEs) were common in patients treated with ICPis. Rheumatologists should be aware of the upcoming challenges in the management of irAEs in a patient receiving treatment with ICPis.

Sustained clinico-radiologic response to anti-cytotoxic T lymphocyte antigen 4 antibody therapy in metastatic myxoid liposarcoma

2016 ◽  
Vol 23 (7) ◽  
pp. 549-551
Author(s):  
Constantin A Dasanu
Keyword(s):  
Metastatic Melanoma ◽  
T Lymphocyte ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Myxoid Liposarcoma ◽  
Effective Control ◽  
Lymphocyte Antigen

Rarity and heterogeneity of sarcomas pose significant challenges in terms of developing new therapies. Therefore, efforts towards studying immunotherapy in sarcomas may provide hope for effective control of this group of devastating cancers. A sustained clinico-radiologic response to the anti-cytotoxic T lymphocyte antigen 4 antibody ipilimumab in a patient with metastatic myxoid liposarcoma is reported. Although the patient was treated with this agent for metastatic melanoma, both his metastatic cancers – melanoma and sarcoma – meaningfully responded to this agent. Consideration of enrolling patients in immunotherapy trials using various immune checkpoint inhibitors, where available, is of paramount importance, especially when facing advanced and/or refractory sarcoma situation.

scholarly journals Neoadjuvant immunotherapy in resectable head and neck cancer: oral cavity carcinoma as a potential research model

2021 ◽  
Vol 13 ◽  
pp. 175883592098406
Author(s):  
Vanesa Gutiérrez Calderón ◽  
Alexandra Cantero González ◽  
Laura Gálvez Carvajal ◽  
Yolanda Aguilar Lizarralde ◽  
Antonio Rueda Domínguez
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Cavity ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Surgical Resection ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Research Model

Squamous cell carcinoma of oral cavity (OCSCC) accounts for approximately 25% of cases of head and neck squamous cell carcinoma (HNSCC). Tobacco and alcohol consumption are the main risk factors for both cancers. Surgical resection, combined with adjuvant radiotherapy or radiochemotherapy in patients with high risk of relapse, is the key element in management in the initial stages. However, despite the availability of aggressive multidisciplinary treatments, advanced resectable OCSCC carries poor prognosis; only half of the patients are disease-free 5 years after the surgery. Immunotherapy based on the use of immune checkpoint inhibitors has been proven to be effective in a wide variety of tumours, including recurrent and metastatic HNSCC. These positive results resulted in investigations into its effectiveness in earlier stages of the disease with OCSCC emerging as an interesting research model because of the accessible location of the tumours. This article reviews the potential advantages of emerging immunotherapeutic agents [mainly monoclonal antibodies against programmed cell death-1 ( PD-1) immune checkpoint inhibitors] as neoadjuvant treatment for OCSCC at locoregional stages as well as the ongoing clinical trials, challenges in evaluating tumour response, and possible predictive biomarkers of response with highlights regarding the role of oral microbiota as modulators of immune response. The efficacy and safety of anti- PD-1 drugs in these patients have been proven in preliminary trials. If there is a decrease in the relapse rate and an improvement in the overall survival after surgical resection in ongoing trials, preoperative immunotherapy may be established as a treatment option for patients with early stages of the disease.

scholarly journals Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1949
Author(s):  
Yawen Dong ◽  
Jeffrey Sum Lung Wong ◽  
Ryohichi Sugimura ◽  
Ka-On Lam ◽  
Bryan Li ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Advanced Hcc ◽  
Oncogenic Pathways ◽  
Vegf Pathway ◽  
And Function ◽  
Endothelial Growth Factor

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

scholarly journals Immune checkpoint inhibitors-related myocarditis in patients with cancer: an analysis of international spontaneous reporting systems

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rulan Ma ◽  
Quanziang Wang ◽  
Deyu Meng ◽  
Kang Li ◽  
Yong Zhang
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Adverse Drug Events ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Reporting Odds Ratio ◽  
Real World Data ◽  
Safety Issues

Abstract Background Immune checkpoint inhibitors-induced myocarditis presents unique clinical challenges. Here, we assessed post-marketing safety of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors by mining the real-world data reported in two international pharmacovigilance databases. Methods We analyzed immune checkpoint inhibitors (ICIs)-associated fatal adverse drug events (ADEs) reports from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) collected from July 1, 2014 to December 31, 2019 and data from EudraVigilance (EV) database accessed on February 29, 2020. Three different data mining approaches were used to detect the signal of fatal myocarditis caused by ICIs. Results Based on 7613 ICIs-related ADEs reported to the EV database and 5786 ICIs-associated ADEs submitted to the FAERS database, the most frequently reported ADE was ipilimumab-related colitis. For myocarditis, nivolumab-associated myocarditis was the most common. Among the five fatal toxic effects associated with ICIs, the lethality rate of myocarditis was the highest. Therefore, we further analyzed ICI-associated myocarditis and found that elderly patients and male patients were more likely to develop ICIs-related myocarditis. The results of signal detection showed that the risk signal of avelumab-related myocarditis detected by reporting odds ratio (ROR) method and proportional reporting ratios (PRR) method was the highest, whereas the signal strength of ipilimumab-related myocarditis detected by Bayesian confidence propagation neural networks (BCPNN) method was the strongest. Conclusion The findings of this study indicated the potential safety issues of developing myocarditis when using ICIs, which were consistent with the results of previous clinical trials and could provide a reference for clinical workers when using ICIs.

scholarly journals 618 Expanding cancer immunotherapy by exploiting recall immunity – A new co-therapy option for checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A648-A648
Author(s):  
Kathlynn Brown ◽  
Michael McGuire ◽  
Anuja Pande ◽  
Indu Venugopal
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Hla Class I ◽  
Tumor Burden ◽  
Class I ◽  
Pancreatic Tumors ◽  
Lymphocyte Response ◽  
Targeting Peptide ◽  
Cytotoxic T Lymphocyte Response

BackgroundImmune checkpoint inhibitors (CIs) have emerged as a revolutionary treatment for several cancer types. Despite significant improvement in prognosis for some patients, there are associated challenges. CIs do not work well on immune-cold tumors, thereby eliciting an insufficient immune response. They are also not as effective in tumors with low mutational burden due to dependance on tumor self-antigens for immune recognition. Therefore, there is a need for a solution to improve the efficacy of CIs to make them applicable to the entire cancer patient population.MethodsTo address this challenge, we have developed a novel immunotherapy capable of delivering previously encountered antigenic peptides specifically to cancer cells and facilitating their presentation through the MHC class I pathway. Our therapy utilizes a synthetic nanoparticle delivery system comprising of three components: a neutral stealth liposome, an encapsulated synthetic immunogenic HLA class I restricted peptide derived from measles virus (MV), and a tumor-targeting peptide on the external surface of the liposome. The targeting peptide results in accumulation of the liposomes specifically inside cancer cells, and facilitates presentation of the MV-derived immunogenic peptides in HLA class I molecules. We refer to this system as TALL (Targeted Antigen Loaded Liposomes). As a result, TALL can generate a strong secondary immune response specifically against the targeted tumor cells in a patient who has been previously vaccinated against or infected by MV. In short, we are attempting to trick the immune system into responding as though the cancer cell is infected with MV without the use of a viral particle. Advantageously, as TALL can provide a potent synthetic antigen specifically to tumor cells, it can convert immune-cold tumors into immune-hot, resulting in a robust cytotoxic T lymphocyte response. Therefore, we conducted pilot studies to determine the efficacy of combining TALL with the anti-PD1 checkpoint inhibitor.ResultsTreatment with TALL alone substantially reduces growth of lung, triple-negative breast, and pancreatic tumors in mice. Treatment with TALL and CI combination therapy showed at least a 10-fold reduction in tumor burden in mice bearing orthotopic breast and pancreatic tumors when compared to using CI treatment alone. The combination treatment also successfully prevented metastasis from occurring.ConclusionsTALL can successfully be used in combination with existing immunotherapies like checkpoint inhibitors, to generate a robust cytotoxic T lymphocyte response directed specifically against the tumor, resulting in a drastic reduction of tumor burden.

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