scholarly journals Severe Gastritis after Administration of Nivolumab and Ipilimumab

2018 ◽  
Vol 11 (2) ◽  
pp. 549-556 ◽  
Author(s):  
Yoshito Nishimura ◽  
Miho Yasuda ◽  
Kazuki Ocho ◽  
Masaya Iwamuro ◽  
Osamu Yamasaki ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Metastatic Malignant Melanoma ◽  
Japanese Woman ◽  
H Pylori ◽  
Inhibitor Treatment

Immune checkpoint inhibitors such as ipilimumab, a cytotoxic T-lymphocyte-associated antigen-4 inhibitor, have been widely used for advanced malignancies. As these inhibitors improve antitumor immunity via T-cell modulation, immune-mediated adverse events associated with T-cell activation, such as colitis, might occur. Herein, we describe a 75-year-old Japanese woman with metastatic malignant melanoma who developed hemorrhagic gastritis after ipilimumab treatment. There was no macroscopic or clinical improvement of gastritis after proton pump inhibitor treatment. However, her condition improved after approximately 3 weeks of corticosteroid therapy and Helicobacter pylori eradication. This case suggests a potential association between severe gastritis and immune checkpoint inhibitor treatment. Although several reports have mentioned ipilimumab-associated colitis, gastritis is considered to be rare. In the present case, H. pylori-associated gastritis might have been exacerbated by the T-cell modulation effect of ipilimumab. To date, no report has clarified the mechanism by which ipilimumab modifies H. pylori infection. The present treatment course provides a helpful perspective for similar cases.

scholarly journals Exclusive Cutaneous and Subcutaneous Sarcoidal Granulomatous Inflammation due to Immune Checkpoint Inhibitors: Report of Two Cases with Unusual Manifestations and Review of the Literature

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Narciss Mobini ◽  
Rummit Dhillon ◽  
Jason Dickey ◽  
Jordan Spoon ◽  
Kaviyon Sadrolashrafi
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Granulomatous Inflammation ◽  
Number Of Patients ◽  
Recent Emergence

Recent emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of cancers and produced prolonged response by boosting the immune system against tumor cells. The primary target antigens are cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), a downregulator of T-cell activation, and programmed cell death-1 receptor (PD-1), a regulator of T-cell proliferation. This enhanced immune response can induce autoimmune adverse effects in many organs. Although skin toxicities are the most common, sarcoidal inflammation with exclusive cutaneous involvement is a rare occurrence with only 6 cases reported to date. We report 2 cases with unusual features. One patient is a female who was treated for metastatic renal cell carcinoma with combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). She developed deep nodules showing sarcoidal dermatitis and panniculitis on histopathologic exam. The second patient is a male with melanoma of eyelid conjunctiva who was treated prophylactically with ipilimumab. He presented with papules/plaques confined to black tattoos, where the biopsy revealed sarcoidal dermatitis. By a comprehensive literature review, we intend to raise awareness about this potential skin side effect in the growing number of patients receiving targeted immunotherapies. It is crucial to have a high index of suspicion and perform timely biopsies to implement appropriate management strategies.

scholarly journals The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

2021 ◽  
Vol 9 ◽  
Author(s):  
Nádia Ghinelli Amôr ◽  
Paulo Sérgio da Silva Santos ◽  
Ana Paula Campanelli
Keyword(s):  
Cell Death ◽  
Monoclonal Antibodies ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Molecules

Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

scholarly journals Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Shuang Qin ◽  
Linping Xu ◽  
Ming Yi ◽  
Shengnan Yu ◽  
Kongming Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Immune Checkpoint Molecules

Abstract The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

Immune checkpoint inhibitors in the treatment of cancer

2021 ◽  
Vol 16 ◽  
Author(s):  
Wissam Zam ◽  
Lina Ali
Keyword(s):  
T Cell Activation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Research Field ◽  
Cell Lung Carcinoma ◽  
Checkpoint Proteins

Background: Immunotherapy drugs, known as immune checkpoint inhibitors (ICIs), work by blocking checkpoint proteins from binding with their partner proteins. The two main pathways that are specifically targeted in clinical practice are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) that showed potent immune-modulatory effects through their function as negative regulators of T cell activation. Methods: In view of the rapid and extensive development of this research field, we conducted a comprehensive review of the literature and update on the use of CTLA-4, PD-1 and PD-L1 targeted therapy in the treatment of several types of cancer including melanoma, non-small-cell lung carcinoma, breast cancer, hepatocellular carcinoma, hodgkin lymphoma, cervical cancer, head and neck squamous cell carcinoma. Results: Based on the last updated list released on March 2019, seven ICIs are approved by the FDA including ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and cemiplimab. Conclusion: This review also highlighted the most common adverse effects caused by ICIs and which affect people in different ways.

CTLA4 and CD47 combinational therapy to extend survival in melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21025-e21025
Author(s):  
Anthony L. Schwartz ◽  
Pulak Nath ◽  
Elizabeth Lessey-Morillon ◽  
Lisa Ridnour ◽  
Michael Allgaeuer ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cell Activation ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Granzyme B ◽  
Suppressor Cells ◽  
Cell Infiltration

e21025 Background: Irradiation (IR) combined with chemotherapy is the post-surgical standard of care treatment for melanoma, but metastasis still results in high mortality rates. Immune checkpoint inhibitors such as cytotoxic T-lymphocyte antigen-4 (CTLA4) have proven effective for immunotherapy of melanoma. CTLA-4 is up-regulated post-T cell activation and blockade enhances tumor responses in immunocompetent rodents and humans. Trials suggest that combinations of immune checkpoint inhibitors are more efficacious than single agents, but tumors remain resistant. We are investigating CD47 blockade for the treatment of cancer. CD47 is frequently elevated in cancers and serves as an inhibitory receptor for thrombospondin-1 on immune cells in the tumor stroma. CD47 blockade on CD8 T or tumor cells significantly enhances immune-targeted tumor cell killing post-IR compared to IR alone. Here we explore the potential for antisense CD47 and anti-CTLA4 therapy alone or in combination with IR using a syngeneic mouse melanoma model. Methods: C57BL/6 mice were inoculated with 1x106B16F10 melanoma cells in the hind limb and treated with 10 Gy IR combined with CTLA4 blocking antibody, CD47 translational blocking morpholino, or the combination of CTLA4/CD47 therapies. Granzyme B along with CD4/CD8 T cell infiltration were examined in tumors. Histology was evaluated for CD3 and necrosis. Results: The combination of CD47/CTLA4 with IR significantly increased survival by 25% compared to IR/CTLA4 alone at 50 days. Granzyme B expression was significantly increased in IR mice with CTLA4/CD47 combination, which correlated with infiltration of CD8+ T cells and a concomitant decrease in Gr1+CD11b suppressor cells compared to controls. In non-IR tumors, histology revealed minimal necrosis, while all IR groups showed increased necrosis. Tumor IR in combination with CTLA4 or CD47 increased immune cell infiltration. However, the combination of IR with CTLA4/CD47 showed widespread necrosis. All groups treated with the CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA4. Conclusions: Results herein suggest IR combined CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response.

Overlapping NMDA-R and GFAP antibody autoimmune encephalitis after Nivolumab therapy

2020 ◽  
pp. 10.1212/CPJ.0000000000001008
Author(s):  
Felipe A. Ayala ◽  
Sean C. Dougherty ◽  
William Swift ◽  
David A. Lapides
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Death Receptor ◽  
Autoimmune Encephalitis ◽  
High Dose ◽  
Cell Lung Carcinoma

Immunotherapy represents a rapidly expanding area of cancer treatment. Immune checkpoint inhibitors (ICIs), monoclonal antibodies including those targeting cytotoxic T-lymphocyte associated protein 4 or the programmed cell death receptor-1 (PD-1) axis, function by removing inhibitory signals on T-cell activation 1. While promoting T-cell mediated tumor lysis, ICI’s alter the immune system’s regulatory checkpoints which can lead to a host of immune-related adverse events (irAEs) 2, 3. Here, we describe a patient treated with nivolumab (Opdivo, Bristol-Myers Squibb, Princeton, New Jersey) for non-small-cell lung carcinoma (NSCLC) over two years who developed overlapping n-methyl-D-aspartate receptor (NMDA-R) and glial fibrillary acidic protein (GFAP) antibody associated autoimmune encephalitis (AE)4. His hospital course was further complicated by dysautonomia responsive to high-dose steroids.

scholarly journals The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy

ESMO Open ◽  
2020 ◽  
Vol 5 (1) ◽  
pp. e000544 ◽  
Author(s):  
Cinzia Solinas ◽  
Chunyan Gu-Trantien ◽  
Karen Willard-Gallo
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Activated T Cells

Inducible T cell costimulator (ICOS, cluster of differentiation (CD278)) is an activating costimulatory immune checkpoint expressed on activated T cells. Its ligand, ICOSL is expressed on antigen-presenting cells and somatic cells, including tumour cells in the tumour microenvironment. ICOS and ICOSL expression is linked to the release of soluble factors (cytokines), induced by activation of the immune response. ICOS and ICOSL binding generates various activities among the diversity of T cell subpopulations, including T cell activation and effector functions and when sustained also suppressive activities mediated by regulatory T cells. This dual role in both antitumour and protumour activities makes targeting the ICOS/ICOSL pathway attractive for enhancement of antitumour immune responses. This review summarises the biological background and rationale for targeting ICOS/ICOSL in cancer together with an overview of the principal ongoing clinical trials that are testing it in combination with anti-cytotoxic T lymphocyte antigen-4 and anti-programmed cell death-1 or anti-programmed cell death ligand-1 based immune checkpoint blockade.

scholarly journals 268 KVA 12.1 a novel fully human anti-VISTA antibody: clinical trial design in monotherapy and in combination with an anti-PD1 antibody

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A291-A291
Author(s):  
Thierry Guillaudeux ◽  
Shawn Iadonato ◽  
Eric Tarcha ◽  
Craig Philips
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Clinical Chemistry ◽  
T Cell Response ◽  
Fixed Dose ◽  
List Type ◽  
Cytokine Levels

BackgroundV-domain Ig Suppressor of T cell Activation (VISTA) is an immune-suppressive checkpoint inhibitor of T cell response. VISTA is expressed in the immuno-suppressive tumor microenvironment, mostly by cells of the myeloid lineage, and its blockade can restore an efficient antitumor immune response especially in hard-to-treat tumors.1 In addition, an increase in VISTA expression has been described after treatment by the current immune checkpoint inhibitors, anti-CTLA-4 or anti-PD1-(L),1 especially in patients refractory to these treatments.2 3 Therefore, VISTA may be involved in a compensatory resistance mechanism to checkpoint inhibitors.MethodsKineta has selected a lead candidate anti-VISTA monoclonal antibody, KVA12.1, after a deep screen of 107 fully human and highly diverse antibodies directed against the extracellular domain of VISTA.ResultsKVA12.1 exhibits high potency and binds to a unique epitope. It restores T cell activation and induces a pro-inflammatory response in in vitro assays. In vivo, in human VISTA knock-in mice, KVA12.1 treatment mediates strong single-agent antitumor activity in multiple syngeneic tumor models and shows enhanced efficacy in combination with either anti-PD-(L)1 or anti-CTLA-4 treatment. Finally, our anti-VISTA antibody was well-tolerated in exploratory toxicology studies in cynomolgus monkey, where hematology and clinical chemistry evaluations as well as clinical observations including monitoring of body weight revealed no indicators of toxicity. Safety endpoints, including the monitoring of cytokine levels related to cytokine release syndrome (CRS), clinical pathology and immunogenicity were evaluated. Cytokine levels associated with CRS (e.g., TNF-alpha, IL-6, IL-1β) were assessed, and none were elevated to levels associated with CRS. These studies provided drug exposures (AUC) well over the expected exposures required for clinical efficacy, and KVA12.1 exhibits a good half-life consistent with other monoclonal check-point inhibitors. We are currently engaged in pre-IND studies and manufacturing of KVA12.1.ConclusionsHere we are presenting the design of a phase 1/2 multicenter, open label, dose escalation and dose expansion study of intravenous infusion of KVA12.1 as a monotherapy and in combination with a fixed dose of an anti-PD1 antibody in patients with advanced refractory or metastatic solid tumors.ReferencesElTanbouly MA, Schaafsma E, Noelle RJ, Lines JL. VISTA: Coming of age as a multi-lineage immune checkpoint. Clin Exp Immunol 2020;200(2):120–130.Kuklinski LF, Yan S, Li Z, Fisher JL, Cheng C, Noelle RJ, Angeles CV, Turk MJ, Ernstoff MS. VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Cancer Immunol Immunother 2018 July;67(7):1113–1121.Kakavand H, Jackett LA, Menzies AM, Gide TN, Carlino MS, Saw RPM, Thompson JF, Wilmott JS, Long GV, Scolyer RA. Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod Pathol 2017 December;30(12):1666–1676.

scholarly journals The Tumor Microenvironment Factors That Promote Resistance to Immune Checkpoint Blockade Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Bonnie L. Russell ◽  
Selisha A. Sooklal ◽  
Sibusiso T. Malindisa ◽  
Lembelani Jonathan Daka ◽  
Monde Ntwasa
Keyword(s):  
Immune System ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Therapy Strategy

Through genetic and epigenetic alterations, cancer cells present the immune system with a diversity of antigens or neoantigens, which the organism must distinguish from self. The immune system responds to neoantigens by activating naïve T cells, which mount an anticancer cytotoxic response. T cell activation begins when the T cell receptor (TCR) interacts with the antigen, which is displayed by the major histocompatibility complex (MHC) on antigen-presenting cells (APCs). Subsequently, accessory stimulatory or inhibitory molecules transduce a secondary signal in concert with the TCR/antigen mediated stimulus. These molecules serve to modulate the activation signal’s strength at the immune synapse. Therefore, the activation signal’s optimum amplitude is maintained by a balance between the costimulatory and inhibitory signals. This system comprises the so-called immune checkpoints such as the programmed cell death (PD-1) and Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and is crucial for the maintenance of self-tolerance. Cancers often evade the intrinsic anti-tumor activity present in normal physiology primarily by the downregulation of T cell activation. The blockade of the immune checkpoint inhibitors using specific monoclonal antibodies has emerged as a potentially powerful anticancer therapy strategy. Several drugs have been approved mainly for solid tumors. However, it has emerged that there are innate and acquired mechanisms by which resistance is developed against these therapies. Some of these are tumor-intrinsic mechanisms, while others are tumor-extrinsic whereby the microenvironment may have innate or acquired resistance to checkpoint inhibitors. This review article will examine mechanisms by which resistance is mounted against immune checkpoint inhibitors focussing on anti-CTL4-A and anti-PD-1/PD-Ll since drugs targeting these checkpoints are the most developed.

Sign in / Sign up

Export Citation Format

Share Document