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.

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.

scholarly journals Development of Nivolumab/Ipilimumab-Associated Autoimmune Nephritis during Steroid Therapy

2021 ◽  
pp. 270-274
Author(s):  
Ellen Gebauer ◽  
Wibke Bechtel-Walz ◽  
Christoph Schell ◽  
Michelle Erbel ◽  
Gerd Walz ◽  
...  
Keyword(s):  
Steroid Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Oral Steroid ◽  
High Dose ◽  
Immune Mediated

Immunotherapy using immune checkpoint inhibitors revolutionized therapies for a variety of malignancies. Nivolumab, an antibody blocking programmed cell death 1 protein, and ipilimumab that blocks cytotoxic T-lymphocyte-associated protein 4 effectively target tumor cells by disinhibiting the endogenous immune response. At the same time, unrestrained T-cell activation may trigger a range of immune-mediated side effects including kidney injury. Steroid therapy constitutes the mainstay of treatment of these adverse events, but dosage, route of administration, and approach to nivolumab re-exposure remain unclear. Here, we report the case of a 72-year-old male patient who developed severe nivolumab/ipilimumab-associated acute kidney injury while on oral steroid therapy for immune-mediated colitis. Acute interstitial nephritis was confirmed by renal biopsy. Administration of high-dose intravenous steroid doses was required to revert declining renal function.

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 Effects of combination treatment with durvalumab plus tremelimumab on the tumor microenvironment in non-small-cell lung carcinoma

2021 ◽  
Author(s):  
Li Cheng ◽  
Todd Creasy ◽  
Fernanda Pilataxi ◽  
Lydia Greenlees ◽  
Luis Vence ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Lung Carcinoma ◽  
Cell Activation ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cancer Stemness ◽  
Cell Lung Carcinoma ◽  
Ifn Γ

AbstractThe rapid development of immune checkpoint blockade (ICB) therapies has revolutionized the cancer treatment landscape and brightened the long-term forecast for many cancer patients. However, the specific genomic and proteomic changes in tumors treated with different ICB treatments have yet to be fully characterized. We treated four non-small-cell lung carcinoma (NSCLC) tumor digests ex vivo with the anti-PD-L1 antibody durvalumab (D) alone or in combination with the anti-CTLA-4 antibody tremelimumab (T) to explore changes in gene and protein expression associated with these ICB therapies. All four tumors showed a robust increase in interferon gamma (IFN-γ) production (100–300% higher than isotype control) in both D- and D + T-treated tumors. Three of the four tumors showed additional increases in IFN-γ production with D + T compared with D (40–70%). A substantial reduction in interleukin 10 (IL-10) was also found in three of the four tumors (reduced to 4–8%) in response to D and D + T. Conventional CD4 + /CD8 + populations and T cell activation markers increased after D and D + T treatment. D and D + T upregulated multiple IPA pathways involving T cell activation. D + T resulted in additional upregulation of Th1/Th2 pathways through a different set of genes, as well as greater reduction in genes involved in epithelial-mesenchymal transition (EMT), angiogenesis, and cancer stemness. Our results demonstrated that D + T augmented the effects of D in the microenvironment of this set of NSCLC tumors. The specific impact of D + T on the regulation of EMT, angiogenesis, and cancer stemness warrants further evaluation in a larger set of tumors.

scholarly journals Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

2021 ◽  
Vol 22 (8) ◽  
pp. 4109
Author(s):  
Mankgopo M. Kgatle ◽  
Tebatso M. G. Boshomane ◽  
Ismaheel O. Lawal ◽  
Kgomotso M. G. Mokoala ◽  
Neo P. Mokgoro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Cancer Control ◽  
Lymphocyte Activation ◽  
Immune Checkpoints ◽  
Mortality And Morbidity ◽  
Domain 3

Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.

scholarly journals CNS demyelination associated with immune dysregulation and a novel CTLA-4 variant

2021 ◽  
pp. 135245852096389
Author(s):  
Stefania Kaninia ◽  
Alexandros Grammatikos ◽  
Kathryn Urankar ◽  
Shelley A Renowden ◽  
Nikunj K Patel ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Novel Treatments ◽  
First Case ◽  
Self Tolerance ◽  
Autoimmune Conditions ◽  
History Of ◽  
Cns Demyelination

Background: The cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway acts as a negative immune regulator of T-cell activation and promotes self-tolerance. Case: We report the first case of biopsy-proven central nervous system inflammatory demyelination in the context of primary immunodeficiency and a novel CTLA-4 variant. Conclusion: This case has significant implications for the development of novel treatments for autoimmune conditions including multiple sclerosis and further emphasises the need for caution with clinical use of CTLA-4 immune checkpoint inhibitors in those with a history of inflammatory demyelination.

scholarly journals Dendritic Cell Tumor Vaccination via Fc Gamma Receptor Targeting: Lessons Learned from Pre-Clinical and Translational Studies

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 409
Author(s):  
Enrique Gómez Alcaide ◽  
Sinduya Krishnarajah ◽  
Fabian Junker
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Lessons Learned ◽  
Antigen Delivery ◽  
Tumor Vaccination ◽  
Translational Studies

Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.

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