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Checkpoint inhibitor

Diana Golden, Antonina Kolmakova, Sunitha Sura, Anthony T Vella, Ani Manichaikul, Xin-Qun Wang, Suzette J Bielinski, Kent D Taylor, Yii-Der Ida Chen, Stephen S Rich, Annabelle Rodriguez
BACKGROUND: The lipoprotein scavenger receptor BI (SCARB1) rs10846744 noncoding variant is significantly associated with atherosclerotic disease independently of traditional cardiovascular risk factors. We identified a potentially novel connection between rs10846744, the immune checkpoint inhibitor lymphocyte activation gene 3 (LAG3), and atherosclerosis. METHODS: In vitro approaches included flow cytometry, lipid raft isolation, phosphosignaling, cytokine measurements, and overexpressing and silencing LAG3 protein...
October 20, 2016: JCI Insight
Viriya Kaewkangsadan, Chandan Verma, Jennifer M Eremin, Gerard Cowley, Mohammed Ilyas, Oleg Eremin
The tumour microenvironment consists of malignant cells, stroma, and immune cells. Prominent tumour-infiltrating lymphocytes (TILs) in breast cancer are associated with a good prognosis and are predictors of a pathological complete response (pCR) with neoadjuvant chemotherapy (NAC). The contribution of different T effector/regulatory cells and cytokines to tumour cell death with NAC requires further characterisation and was investigated in this study. Breast tumours from 33 women with large and locally advanced breast cancers undergoing NAC were immunohistochemically (intratumoural, stromal) assessed for T cell subsets and cytokine expression using labelled antibodies, employing established semiquantitative methods...
2016: Journal of Immunology Research
Melissa A Wilson, Kelly Guld, Steven Galetta, Ryan D Walsh, Julia Kharlip, Madhura Tamhankar, Suzanne McGettigan, Lynn M Schuchter, Leslie A Fecher
BACKGROUND: Ipilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs). CASE PRESENTATION: Here we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment...
2016: Journal for Immunotherapy of Cancer
Michael Ong, Andrea Marie Ibrahim, Samuel Bourassa-Blanchette, Christina Canil, Todd Fairhead, Greg Knoll
BACKGROUND: Nivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer...
2016: Journal for Immunotherapy of Cancer
Sasha E Stanton, Mary L Disis
Tumor infiltrating lymphocytes (TIL) play an essential role in mediating response to chemotherapy and improving clinical outcomes in all subtypes of breast cancer. Triple negative breast cancers (TN) are most likely to have tumors with >50 % lymphocytic infiltrate, termed lymphocyte predominant breast cancer, and derive the greatest survival benefit from each 10 % increase in TIL. The majority of HER2(+) breast cancers have similar level of immune infiltrate as TN breast cancer yet the presence of TILs has not shown the same survival benefit...
2016: Journal for Immunotherapy of Cancer
Parminder Singh, Peter Black
OBJECTIVE: Checkpoint inhibitors have rapidly become a standard treatment option for metastatic urothelial carcinoma. A wave of enthusiasm for these drugs has pushed them also into the setting of localized bladder cancer, including both non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive disease bladder cancer (MIBC). Here, we aimed to review the emerging role of checkpoint inhibition in localized bladder cancer. METHODS: We reviewed the current treatment landscape for both NMIBC and MIBC and established a significant unmet clinical need for novel therapies...
October 21, 2016: Urologic Oncology
Bella H V Nguyen, James Kuo, Anadian Budiman, Hayden Christie, Sayed Ali
Immune checkpoint inhibitors have changed the landscape of the treatment of multiple solid malignancies, and have been used increasingly in the recent years. Although usually well tolerated, given the relative inexperience of using immune checkpoint inhibitors, we are still learning of new side effects from the treatment. We report on two cases of ocular myasthenia gravis that occurred after treatment with pembrolizumab, an antiprogrammed-death (anti-PD1) monoclonal antibody for advanced melanoma in responding patients...
October 21, 2016: Melanoma Research
Sandra Demaria, C Norman Coleman, Silvia C Formenti
Immune checkpoint inhibitors are effective in cancer treatment. A pre-existing immune response demonstrated by significant pretreatment tumor lymphocytic infiltration is a pre-requisite for response. Within such infiltrated tumors, referred as "hot", immune checkpoint inhibitors rescue anti-tumor T cells activity. In contrast, "cold" tumors lack lymphocytic infiltration and are refractory to immunotherapy. Preclinical data show that radiotherapy sensitizes refractory tumors to immune checkpoint inhibitors by recruiting anti-tumor T cells...
June 2016: Trends in Cancer
Jong Chul Park, Noah M Hahn
Tremendous advances in our understanding of the tumor immunology and molecular biology of urothelial carcinoma (UC) have led to the recent approval of immunotherapy as a novel option for patients with UC with advanced disease. Despite the promising data of novel immune checkpoint inhibitors, only a small subset of patients with UC achieves durable remissions. Because an optimal antitumor response requires coordination of multiple immune, tumor, and microenvironment effector cells, novel approaches targeting distinct mechanisms of action likely in combination are needed...
October 20, 2016: Urologic Oncology
Taofeek K Owonikoko, Mukesh Kumar, Shu Yang, Alice O Kamphorst, Rathi N Pillai, Rama Akondy, Vivek Nautiyal, Monica S Chatwal, Wendy M Book, Anurag Sahu, Gabriel L Sica, Rafi Ahmed, Suresh S Ramalingam
INTRODUCTION: The increased availability of immunotherapeutic agents for the treatment of a wide array of cancer in the general oncology practice setting will reveal rare and unique toxicities. MATERIALS AND METHODS: The mechanism of cardiac allograft rejection in the context of PD-1 antibody therapy was explored in a patient with cutaneous squamous cell cancer complicating long-standing cardiac allograft. Immune cell infiltrate in the myocardium and peripheral blood lymphocyte repertoire were assessed using myocardial biopsy and temporal analysis of peripheral blood samples...
October 22, 2016: Cancer Immunology, Immunotherapy: CII
Ronan J Kelly, Thomas J Smith
No abstract text is available yet for this article.
November 2016: Journal of Thoracic Oncology
Junsik Park, Minsuk Kwon, Eui-Cheol Shin
During immune responses antigen-specific T cells are regulated by several mechanisms, including through inhibitory receptors and regulatory T cells, to avoid excessive or persistent immune responses. These regulatory mechanisms, which are called 'immune checkpoints', suppress T cell responses, particularly in patients with chronic viral infections and cancer where viral antigens or tumor antigens persist for a long time and contribute to T cell exhaustion. Among these regulatory mechanisms, cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) are the most well-known receptors and both have been targeted for drug development...
October 21, 2016: Archives of Pharmacal Research
Liqing Wang, Suresh Kumar, Satinder Dahiya, Feng Wang, Jian Wu, Kheng Newick, Rongxiang Han, Arabinda Samanta, Ulf H Beier, Tatiana Akimova, Tricia R Bhatti, Benjamin Nicholson, Mathew P Kodrasov, Saket Agarwal, David E Sterner, Wei Gu, Joseph Weinstock, Tauseef R Butt, Steven M Albelda, Wayne W Hancock
Foxp3+ T-regulatory (Treg) cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or "secondary" modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3...
October 15, 2016: EBioMedicine
C Franklin, E Livingstone, A Roesch, B Schilling, D Schadendorf
Malignant melanoma contributes the majority of skin cancer related deaths and shows an increasing incidence in the past years. Despite all efforts of early diagnosis, metastatic melanoma still has a poor prognosis and remains a challenge for treating physicians. In recent years, improved knowledge of the pathophysiology and a better understanding of the role of the immune system in tumour control have led to the development and approval of several immunotherapies. Monoclonal antibodies against different immune checkpoints have been revolutionizing the treatment of metastatic and unresectable melanoma...
September 2, 2016: European Journal of Surgical Oncology
Erika Heninger, Timothy E G Krueger, Stephanie M Thiede, Jamie M Sperger, Brianna L Byers, Madison R Kircher, David Kosoff, Bing Yang, David F Jarrard, Douglas G McNeel, Joshua M Lang
Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2'-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589...
October 17, 2016: Oncotarget
Nitin Chakravarti, Doina Ivan, Van A Trinh, Isabella C Glitza, Jonathan L Curry, Carlos Torres-Cabala, Michael T Tetzlaff, Roland L Bassett, Victor G Prieto, Wen-Jen Hwu
Ipilimumab, a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), is the first immune checkpoint inhibitor approved for the treatment of unresectable melanoma on the basis of its overall survival (OS) benefit. However, ipilimumab is associated with significant immune-related adverse events. We hypothesized that biomarker exploration of pretreatment tumor samples and correlation with clinical outcome would enable patient selection with an increased benefit/risk ratio for ipilimumab therapy...
October 20, 2016: Melanoma Research
Chee Khoon Lee, Johnathan Man, Sally Lord, Matthew Links, Val Gebski, Tony Mok, James Chih-Hsin Yang
INTRODUCTION: We performed a meta-analysis to assess the role of immune-checkpoint inhibitors as second-line therapy in epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC). METHODS: Randomized trials comparing immune-checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation defined subgroups...
October 17, 2016: Journal of Thoracic Oncology
Young Kwang Chae, Lauren Chiec, Nisha Mohindra, Ryan Gentzler, Jyoti Patel, Francis Giles
Immune checkpoint inhibitors such as pembrolizumab, ipilimumab, and nivolumab, now FDA-approved for use in treating several types of cancer, have been associated with immune-related adverse effects. Specifically, the antibodies targeting the programmed-cell death-1 immune checkpoint, pembrolizumab and nivolumab, have been rarely reported to induce the development of type 1 diabetes mellitus. Here we describe a case of a patient who developed antibody-positive type 1 diabetes mellitus following treatment with pembrolizumab in combination with systemic chemotherapy for metastatic adenocarcinoma of the lung...
October 19, 2016: Cancer Immunology, Immunotherapy: CII
Noriyasu Chika, Minoru Fukuchi, Okihide Suzuki, Tetsuya Ito, Azusa Yamamoto, Toru Ishiguro, Youichi Kumagai, Keiichiro Ishibashi, Erito Mochiki, Hideyuki Ishida
The loss of mismatch repair(MMR)function as a result of MLH1 promoter methylation is closely correlated with high frequency microsatellite instability, and tumors with such characteristics are resistant to anticancer drugs such as 5-FU. We examined the incidence and characteristics of deficient MMR(dMMR)in elderly gastric cancer patients by performing a comprehensive immunohistochemical screening. The study was conducted in 199 patients diagnosed with gastric cancer, aged 75 years or older, who underwent a gastrectomy between April 2005 and January 2014...
October 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Tsutomu Takeda, Nobuaki Hattori, Takashi Takeda, Takehiro Noda, Hiroko Takeda
We treated 19 cancer patients with cancer types other than melanoma and lung cancer with immune checkpoint inhibitors, between June 2015 and April 2016. We administered nivolumab at 2-3mg/kg bw every 2-3 weeks. One patient received 14 doses, 5 received 6 doses, 3 received 5 doses, 3 received 4 doses, and 3 received 3 doses. Three remarkably effective responses were seen in cases of pancreatic cancer, esophageal cancer, and brain malignant lymphoma. In every effective case, dendritic cell therapy was administered prior to nivolumab...
October 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
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