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https://www.readbyqxmd.com/read/28723667/resistance-to-ctla-4-checkpoint-inhibition-reversed-through-selective-elimination-of-granulocytic-myeloid-cells
#1
Paul E Clavijo, Ellen C Moore, Jianhong Chen, Ruth J Davis, Jay Friedman, Young Kim, Carter Van Waes, Zhong Chen, Clint T Allen
PURPOSE: Local immunosuppression remains a critical problem that limits clinically meaningful response to checkpoint inhibition in patients with head and neck cancer. Here, we assessed the impact of MDSC elimination on responses to CTLA-4 checkpoint inhibition. EXPERIMENTAL DESIGN: Murine syngeneic carcinoma immune infiltrates were characterized by flow cytometry. Granulocytic MDSCs (gMDSCs) were depleted and T-lymphocyte antigen-specific responses were measured...
June 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28721449/role-of-regulatory-t-cells-in-acute-myeloid-leukemia-patients-undergoing-relapse-preventive-immunotherapy
#2
Frida Ewald Sander, Malin Nilsson, Anna Rydström, Johan Aurelius, Rebecca E Riise, Charlotta Movitz, Elin Bernson, Roberta Kiffin, Anders Ståhlberg, Mats Brune, Robin Foà, Kristoffer Hellstrand, Fredrik B Thorén, Anna Martner
Regulatory T cells (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3(+)CD25(high)CD4(+) Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival...
July 18, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28719552/immune-checkpoint-inhibitors-in-organ-transplant-patients
#3
Adam S Kittai, Hayden Oldham, Jeremy Cetnar, Matthew Taylor
Modulation of T-cell activity through blockade of coinhibitory molecules has revolutionized the treatment of various malignancies. Several immune checkpoint inhibitors are currently Food and Drug Administration approved which target various coinhibitory pathways including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 receptor (PD-1), and programmed cell death ligand-1. Clinical trials that lead to the Food and Drug Administration approval of these agents often excluded patients with an organ transplant...
July 17, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28716652/toxicity-profiles-of-immunotherapy
#4
REVIEW
Sophie Cousin, Antoine Italiano
Immunotherapies are changing the landscape of advanced solid tumor treatment. These therapies have different mechanisms of action and include oncolytic viruses, checkpoint inhibitors, such as CTLA-4 or PD1/PD-L1 monoclonal antibodies, and CSF-1R antibodies. Given the growing therapeutic impact of these agents in oncology, it is important to better understand their properties. Immunotherapies generate new toxicity profiles that are called immune-related adverse events and require specific management. This review focuses on the mechanisms of action of such side effects, as well as their description and their general management...
July 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28716137/progressive-hypoventilation-due-to-mixed-cd8-and-cd4-lymphocytic-polymyositis-following-tremelimumab-durvalumab-treatment
#5
Sooraj John, Scott J Antonia, Trevor A Rose, Robert P Seifert, Barbara A Centeno, Aaron S Wagner, Ben C Creelan
BACKGROUND: The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. CASE PRESENTATION: We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature...
July 18, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28714866/ibrutinib-treatment-improves-t-cell-number-and-function-in-cll-patients
#6
Meixiao Long, Kyle Beckwith, Priscilla Do, Bethany L Mundy, Amber Gordon, Amy M Lehman, Kami J Maddocks, Carolyn Cheney, Jeffrey A Jones, Joseph M Flynn, Leslie A Andritsos, Farrukh Awan, Joseph A Fraietta, Carl H June, Marcela V Maus, Jennifer A Woyach, Michael A Caligiuri, Amy J Johnson, Natarajan Muthusamy, John C Byrd
BACKGROUND: Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS: Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially...
July 17, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28707078/ctla-4-expression-in-the-non-small-cell-lung-cancer-patient-tumor-microenvironment-diverging-prognostic-impact-in-primary-tumors-and-lymph-node-metastases
#7
Erna-Elise Paulsen, Thomas K Kilvaer, Mehrdad Rakaee, Elin Richardsen, Sigurd M Hald, Sigve Andersen, Lill-Tove Busund, Roy M Bremnes, Tom Donnem
The immune checkpoint receptor CTLA-4 plays a crucial part in negatively regulating T cell activation and maintaining self-tolerance. It is frequently overexpressed in a variety of malignancies, yet its prognostic impact in non-small cell lung cancer (NSCLC) remains unclear. We constructed tissue microarrays from tumor tissue samples and evaluated the immunohistochemical expression of CTLA-4 in 536 patients with primary resected stage I-IIIA NSCLC. Expression of CTLA-4 was analyzed in tumor and stromal primary tumor tissue and in locoregional metastatic lymph nodes...
July 13, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28693793/biomarkers-of-response-to-pd-1-pd-l1-inhibition
#8
REVIEW
Saman Maleki Vareki, Carmen Garrigós, Ignacio Duran
Immunotherapy is a promising treatment strategy for cancer that has recently shown unprecedented survival benefits in selected patients. A number of immunomodulatory agents that target immune system checkpoints such as the cytotoxic T-lymphocyte antigen 4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1), have received regulatory approval for the treatment of multiple cancers including malignant melanoma, non-small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, and recurrent or metastatic head and neck squamous cell carcinoma...
August 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28692319/low-energy-x-ray-grenz-ray-treatment-of-purified-islets-prior-to-allotransplant-markedly-decreases-passenger-leukocyte-populations
#9
Rena Pawlick, Boris Gala-Lopez, Andrew R Pepper, Nasser Abualhassan, Antonio Bruni, Kunimasa Suzuki, Gina Rayat, John F Elliott, A M James Shapiro
Grenz rays, or minimally penetrating X-rays, are known to be an effective treatment of certain recalcitrant immune-mediated skin diseases, but their use in modulating allograft rejection has not been tested. We examined the capacity of grenz ray treatment to minimize islet immunogenicity and extend allograft survival in a mouse model. In a preliminary experiment, 1 of 3 immunologically intact animals demonstrated long-term acceptance of their grenz ray treated islet allograft. Further experiments revealed that 28...
July 4, 2017: Islets
https://www.readbyqxmd.com/read/28690075/tumor-microenvironment-changes-leading-to-resistance-of-immune-checkpoint-inhibitors-in-metastatic-melanoma-and-strategies-to-overcome-resistance
#10
REVIEW
Bhargavi Pulluri, Abhijeet Kumar, Montaser Shaheen, Joanne Jeter, Srinath Sundararajan
Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy...
July 6, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28689073/endocrine-related-adverse-events-associated-with-immune-checkpoint-blockade-and-expert-insights-on-their-management
#11
REVIEW
Mario Sznol, Michael A Postow, Marianne J Davies, Anna C Pavlick, Elizabeth R Plimack, Montaser Shaheen, Colleen Veloski, Caroline Robert
Agents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs...
June 22, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28688973/pd-1-pd-l1-checkpoint-blockades-in-non-small-cell-lung-cancer-new-development-and-challenges
#12
Xiangjiao Meng, Yanli Liu, Jianjun Zhang, Feifei Teng, Ligang Xing, Jinming Yu
PD-1/PD-L1 checkpoint blockades have dramatically changed the landscape for second-line treatment of non-small cell lung cancer (NSCLC). Based on the promising results of Keynote-024 presented so far, pembrolizumab has been approved as first-line treatment for advanced PD-L1 positive NSCLC patients. However, overall response rate (ORR) is limited to PD-1/PD-L1 checkpoint blockades when used as single agent. Combining with chemotherapy, anti-CTLA-4 antibodies, targeted therapy, radiotherapy or other treatment options is perceived as an appealing method aimed at achieving higher efficacy...
July 6, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28684198/flow-cytometry-based-diagnosis-of-primary-immunodeficiency-diseases
#13
REVIEW
Hirokazu Kanegane, Akihiro Hoshino, Tsubasa Okano, Takahiro Yasumi, Taizo Wada, Hidetoshi Takada, Satoshi Okada, Motoi Yamashita, Tzu-Wen Yeh, Ryuta Nishikomori, Masatoshi Takagi, Kohsuke Imai, Hans D Ochs, Tomohiro Morio
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs...
July 3, 2017: Allergology International: Official Journal of the Japanese Society of Allergology
https://www.readbyqxmd.com/read/28683958/-adverse-effects-of-immune-checkpoint-inhibitors-used-to-treat-melanoma-and-other-cancer
#14
Claire Jacquin-Porretaz, Charlée Nardin, Eve Puzenat, Blandine Roche-Kubler, François Aubin
Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers and metastatic renal cancer. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events that may be life threatening if not anticipated and managed appropriately. This new family of dysimmune toxicities remains largely unknown to the broad oncology community...
July 3, 2017: La Presse Médicale
https://www.readbyqxmd.com/read/28680882/immunotherapy-for-patients-with-advanced-urothelial-cancer-current-evidence-and-future-perspectives
#15
REVIEW
Clizia Zichi, Marcello Tucci, Gianmarco Leone, Consuelo Buttigliero, Francesca Vignani, Daniele Pignataro, Giorgio V Scagliotti, Massimo Di Maio
In recent years, immunotherapy has produced encouraging results in a rapidly increasing number of solid tumors. The responsiveness of bladder cancer to immunotherapy was first established in nonmuscle invasive disease in 1976 with intravesical instillations of bacillus Calmette-Guérin (BCG). Very recently immune checkpoint inhibitors demonstrated good activity and significant efficacy in metastatic disease. In particular the best results were obtained with programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors, but many other immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibodies, are currently under investigation in several trials...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28679955/adoptively-transferred-v%C3%AE-9v%C3%AE-2-t-cells-show-potent-antitumor-effects-in-a-preclinical-b-cell-lymphomagenesis-model
#16
Nicholas A Zumwalde, Akshat Sharma, Xuequn Xu, Shidong Ma, Christine L Schneider, James C Romero-Masters, Amy W Hudson, Annette Gendron-Fitzpatrick, Shannon C Kenney, Jenny E Gumperz
A central issue for adoptive cellular immunotherapy is overcoming immunosuppressive signals to achieve tumor clearance. While γδ T cells are known to be potent cytolytic effectors that can kill a variety of cancers, it is not clear whether they are inhibited by suppressive ligands expressed in tumor microenvironments. Here, we have used a powerful preclinical model where EBV infection drives the de novo generation of human B cell lymphomas in vivo, and autologous T lymphocytes are held in check by PD-1/CTLA-4-mediated inhibition...
July 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28679835/new-b7-family-checkpoints-in-human-cancers
#17
REVIEW
Ling Ni, Chen Dong
T cells are the main effector cells in immune response against tumors. The activation of T cells is regulated by the innate immune system through positive and negative costimulatory molecules. Targeting immune checkpoint regulators such as programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) and CTL antigen 4 (CTLA-4) has achieved notable benefit in a variety of cancers, which leads to multiple clinical trials with antibodies targeting the other related B7/CD28 family members. Recently, five new B7 family ligands, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7, were identified...
July 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28679300/the-emerging-role-of-immune-checkpoint-based-approaches-in-aml-and-mds
#18
Prajwal Boddu, Hagop Kantarjian, Guillermo Garcia-Manero, James Allison, Padmanee Sharma, Naval Daver
The development of immune checkpoint inhibitors represents a major breakthrough in the field of cancer therapeutics. Pursuant to their success in melanoma and numerous solid tumor malignancies, these agents are being investigated in hematological malignancies including acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Although AML/MDS have traditionally been considered to be less immunogenic than solid tumor malignancies, recent pre-clinical models suggest a therapeutic role for immune checkpoint inhibition in these diseases...
July 6, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28679287/the-safety-of-nivolumab-for-the-treatment-of-metastatic-melanoma
#19
James Larkin, Aine O'Reilly
Nivolumab, a human IgG4 monoclonal antibody directed against PD-1, is a checkpoint inhibitor that is licenced in the treatment of metastatic melanoma either as a monotherapy or in combination with ipilimumab, a CTLA-4 inhibitor. The introduction of immune checkpoint inhibitors to the therapeutic landscape has dramatically altered outcomes in a proportion of patients with metastatic melanoma. Immune checkpoint inhibitors result in a toxicity profile that is distinct from that of chemotherapy or targeted therapy based on their immunomodulatory mechanism and similarly can result in patterns of response that are unique...
July 6, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28677152/significant-augmentation-of-regulatory-t-cell-numbers-occurs-during-the-early-neonatal-period
#20
Seiichi Hayakawa, Norioki Ohno, Satoshi Okada, Masao Kobayashi
Regulatory T cells (Tregs) control immune responses by suppressing various inflammatory cells. Tregs in newborn babies may play an important role in preventing excessive immune responses during their environmental change. We examined the number and phenotype of Tregs during the neonatal period in 49 newborn babies. Tregs were characterized by flow cytometry using cord blood (CB) and peripheral blood (PB) from the early (7-8 days after birth) and late (2-4 weeks after birth) neonatal periods. CD4(+) Foxp3(+) T cells were classified into resting Tregs (CD45RA(+) Foxp3(low) ), activated Tregs (CD45RA(-) Foxp3(high) ), and newly activated T cells (CD45RA(-) Foxp3(low) )...
July 5, 2017: Clinical and Experimental Immunology
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