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immune-checkpoint blockade

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https://www.readbyqxmd.com/read/28428884/phase-i-clinical-trial-of-combination-imatinib-and-ipilimumab-in-patients-with-advanced-malignancies
#1
Matthew J Reilley, Ann Bailey, Vivek Subbiah, Filip Janku, Aung Naing, Gerald Falchook, Daniel Karp, Sarina Piha-Paul, Apostolia Tsimberidou, Siqing Fu, JoAnn Lim, Stacie Bean, Allison Bass, Sandra Montez, Luis Vence, Padmanee Sharma, James Allison, Funda Meric-Bernstam, David S Hong
BACKGROUND: Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer. METHODS: Primary objective of the dose-escalation study (3 + 3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28427523/combination-of-immune-checkpoint-inhibitors-and-radiotherapy-review-of-the-literature
#2
REVIEW
Alessandro Sindoni, Fabio Minutoli, Giorgio Ascenti, Stefano Pergolizzi
Literature experiences in cancer treatment usually deal with either targeting the tumour cell or the immune system, which often fail to reach the curative purposes in many solid tumours. On the other hand, one mechanism of radiation-induced tumour control is the activation of the adaptive immune system by tumour antigen release following radiotherapy. So, combining radiation therapy with immune checkpoint blockade treatment at the same time may represent a way to stimulate the adaptive immune system, with further amplification of immune responses reached through systemic immune checkpoint blockade...
May 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28427434/adenovirus-mediated-cd40l-gene-transfer-increases-teffector-tregulatory-cell-ratio-and-upregulates-death-receptors-in-metastatic-melanoma-patients
#3
A Schiza, J Wenthe, S Mangsbo, E Eriksson, Anders Nilsson, T H Tötterman, A Loskog, G Ullenhag
BACKGROUND AND AIMS: Malignant melanoma is an aggressive tumor sensitive for immunotherapy such as checkpoint blockade antibodies. Still, most patients with late stage disease do not respond, and the side effects can be severe. Stimulation of the CD40 pathway to initiate anti-tumor immunity is a promising alternative. Herein, we demonstrate immune profiling data from melanoma patients treated with an adenovirus-based CD40 ligand gene therapy (AdCD40L). METHODS: Peripheral blood mononuclear cells and plasma were collected from malignant melanoma patients (n = 15) enrolled in a phase I/IIa study investigating intratumoral delivery of AdCD40L with or without low dose cyclophosphamide...
April 20, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28424516/slamf7-is-critical-for-phagocytosis-of-haematopoietic-tumour-cells-via-mac-1-integrin
#4
Jun Chen, Ming-Chao Zhong, Huaijian Guo, Dominique Davidson, Sabrin Mishel, Yan Lu, Inmoo Rhee, Luis-Alberto Pérez-Quintero, Shaohua Zhang, Mario-Ernesto Cruz-Munoz, Ning Wu, Donald C Vinh, Meenal Sinha, Virginie Calderon, Clifford A Lowell, Jayne S Danska, André Veillette
Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Phagocytosis by macrophages plays a critical role in cancer control. Therapeutic blockade of signal regulatory protein (SIRP)-α, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo, suggesting that blockade of the SIRPα-CD47 checkpoint could be useful in treating human cancer...
April 19, 2017: Nature
https://www.readbyqxmd.com/read/28423034/elevated-frequencies-of-cd8-t-cells-expressing-pd-1-ctla-4-and-tim-3-within-tumour-from-perineural-squamous-cell-carcinoma-patients
#5
Richard Linedale, Campbell Schmidt, Brigid T King, Annabelle G Ganko, Fiona Simpson, Benedict J Panizza, Graham R Leggatt
Perineural spread of tumour cells along cranial nerves is a severe complication of primary cutaneous squamous cell carcinomas of the head and neck region. While surgical excision of the tumour is the treatment of choice, removal of all the tumour is often complicated by the neural location and recurrence is frequent. Non-invasive immune treatments such as checkpoint inhibitor blockade may be useful in this set of tumours although little is understood about the immune response to perineural spread of squamous cell carcinomas...
2017: PloS One
https://www.readbyqxmd.com/read/28421272/-the-pathology-of-adverse-events-with-immune-checkpoint-inhibitors
#6
V H Koelzer, K Glatz, L Bubendorf, A Weber, A Gaspert, G Cathomas, A Lugli, A Zippelius, W Kempf, K D Mertz
BACKGROUND: Immunotherapy has gained importance with the development of new effective cancer treatments. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote T‑cell mediated tumor immune rejection. Checkpoint blockade also carries the risk of inducing autoimmune reactions ("immune related adverse events", irAEs). The diagnosis and classification of irAEs constitute a new and important field in pathology. AIM: Practice-oriented review of the diagnosis and classification of irAEs...
April 18, 2017: Der Pathologe
https://www.readbyqxmd.com/read/28421069/engineering-chimeric-antigen-receptor-t-cells-for-racing-in-solid-tumors-don-t-forget-the-fuel
#7
REVIEW
Melita Irving, Romain Vuillefroy de Silly, Kirsten Scholten, Nahzli Dilek, George Coukos
T-cells play a critical role in tumor immunity. Indeed, the presence of tumor-infiltrating lymphocytes is a predictor of favorable patient prognosis for many indications and is a requirement for responsiveness to immune checkpoint blockade therapy targeting programmed cell death 1. For tumors lacking immune infiltrate, or for which antigen processing and/or presentation has been downregulated, a promising immunotherapeutic approach is chimeric antigen receptor (CAR) T-cell therapy. CARs are hybrid receptors that link the tumor antigen specificity and affinity of an antibody-derived single-chain variable fragment with signaling endodomains associated with T-cell activation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28420421/analysis-of-100-000-human-cancer-genomes-reveals-the-landscape-of-tumor-mutational-burden
#8
Zachary R Chalmers, Caitlin F Connelly, David Fabrizio, Laurie Gay, Siraj M Ali, Riley Ennis, Alexa Schrock, Brittany Campbell, Adam Shlien, Juliann Chmielecki, Franklin Huang, Yuting He, James Sun, Uri Tabori, Mark Kennedy, Daniel S Lieber, Steven Roels, Jared White, Geoffrey A Otto, Jeffrey S Ross, Levi Garraway, Vincent A Miller, Phillip J Stephens, Garrett M Frampton
BACKGROUND: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. METHODS: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome...
April 19, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28418281/programmed-death-ligand-1-pd-l1-expression-in-the-programmed-death-receptor-1-pd-1-pd-l1-blockade-a-key-player-against-various-cancers
#9
Jian Guan, Khin Sandar Lim, Tarek Mekhail, Chung-Che Chang
CONTEXT: - Immune checkpoint pathways, including programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) signaling pathway, which are important in mediating self-tolerance and controlling self-damage, can sometimes be manipulated by cancer cells to evade immune surveillance. Recent clinical trials further demonstrate the efficacy of PD-1/PD-L1-targeted therapy in various cancers and reveal a new era of cancer immunotherapy. OBJECTIVE: - To review the mechanism of the PD-1/PD-L1 signaling pathway, the regulation of this pathway, PD-1/PD-L1 as a predictive and/or prognostic marker in various cancers, and strategies of measuring PD-L1 expression...
April 18, 2017: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/28416753/synergistic-effects-of-the-immune-checkpoint-inhibitor-ctla-4-combined-with-the-growth-inhibitor-lycorine-in-a-mouse-model-of-renal-cell-carcinoma
#10
Xiezhao Li, Peng Xu, Chongshan Wang, Naijin Xu, Abai Xu, Yawen Xu, Takuya Sadahira, Motoo Araki, Koichiro Wada, Eiji Matsuura, Masami Watanabe, Junxia Zheng, Pinghua Sun, Peng Huang, Yasutomo Nasu, Chunxiao Liu
Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation)...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28411205/vista-upregulation-may-promote-resistance-to-ctla-4-blockade
#11
(no author information available yet)
CTLA-4 blockade with ipilimumab activates the immune inhibitory VISTA checkpoint in prostate cancer.
April 14, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28410210/non-invasive-assessment-of-murine-pd-l1-levels-in-syngeneic-tumor-models-by-nuclear-imaging-with-nanobody-tracers
#12
Katrijn Broos, Marleen Keyaerts, Quentin Lecocq, Dries Renmans, Tham Nguyen, David Escors, Adrian Liston, Geert Raes, Karine Breckpot, Nick Devoogdt
Blockade of the inhibitory PD-1/PD-L1 immune checkpoint axis is a promising cancer treatment. Nonetheless, a significant number of patients and malignancies do not respond to this therapy. To develop a screen for response to PD-1/PD-L1 inhibition, it is critical to develop a non-invasive tool to accurately assess dynamic immune checkpoint expression. Here we evaluated non-invasive SPECT/CT imaging of PD-L1 expression, in murine tumor models with varying PD-L1 expression, using high affinity PD-L1-specific nanobodies (Nbs)...
March 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408386/increased-pd-1-and-tim-3-tils-during-cetuximab-therapy-inversely-correlates-with-response-in-head-and-neck-cancer-patients
#13
Hyun-Bae Jie, Raghvendra M Srivastava, Athanassios Argiris, Julie E Bauman, Lawrence P Kane, Robert L Ferris
Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8+ tumorinfiltrating lymphocytes (TILs) and compared them to those of peripheral blood T lymphocytes (PBLs) in patients with head and neck cancer (HNSCC) during cetuximab therapy...
April 13, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28407116/lethal-aplastic-anemia-caused-by-dual-immune-checkpoint-blockade-in-metastatic-melanoma
#14
H Helgadottir, L Kis, P Ljungman, J Larkin, R Kefford, P A Ascierto, J Hansson, G Masucci
No abstract text is available yet for this article.
April 12, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28406723/aspirin-use-and-colorectal-cancer-survival-according-to-tumor-cd274-programmed-cell-death-1-ligand-1-expression-status
#15
Tsuyoshi Hamada, Yin Cao, Zhi Rong Qian, Yohei Masugi, Jonathan A Nowak, Juhong Yang, Mingyang Song, Kosuke Mima, Keisuke Kosumi, Li Liu, Yan Shi, Annacarolina da Silva, Mancang Gu, Wanwan Li, NaNa Keum, Xuehong Zhang, Kana Wu, Jeffrey A Meyerhardt, Edward L Giovannucci, Marios Giannakis, Scott J Rodig, Gordon J Freeman, Daniel Nevo, Molin Wang, Andrew T Chan, Charles S Fuchs, Reiko Nishihara, Shuji Ogino
Purpose Blockade of the programmed cell death 1 (PDCD1, PD-1) immune checkpoint pathway can improve clinical outcomes in various malignancies. Evidence suggests that aspirin (a widely used nonsteroidal anti-inflammatory drug) not only prolongs colorectal cancer survival, but can also activate T cell-mediated antitumor immunity and synergize with immunotherapy through inhibition of prostaglandin E2 production. We hypothesized that the survival benefit associated with aspirin might be stronger in colorectal carcinoma with a lower CD274 (PDCD1 ligand 1, PD-L1) expression level that resulted in lower signaling of the immune checkpoint pathway...
April 13, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28405498/cergutuzumab-amunaleukin-cea-il2v-a-cea-targeted-il-2-variant-based-immunocytokine-for-combination-cancer-immunotherapy-overcoming-limitations-of-aldesleukin-and-conventional-il-2-based-immunocytokines
#16
Christian Klein, Inja Waldhauer, Valeria G Nicolini, Anne Freimoser-Grundschober, Tapan Nayak, Danielle J Vugts, Claire Dunn, Marije Bolijn, Jörg Benz, Martine Stihle, Sabine Lang, Michaele Roemmele, Thomas Hofer, Erwin van Puijenbroek, David Wittig, Samuel Moser, Oliver Ast, Peter Brünker, Ingo H Gorr, Sebastian Neumann, Maria Cristina de Vera Mudry, Heather Hinton, Flavio Crameri, Jose Saro, Stefan Evers, Christian Gerdes, Marina Bacac, Guus van Dongen, Ekkehard Moessner, Pablo Umaña
We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the therapeutic index of IL-2 therapy by (a) preferential retention at the tumor by having a lower dissociation rate from CEA-expressing cancer cells vs...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28404865/dual-angiopoietin-2-and-vegfa-inhibition-elicits-antitumor-immunity-that-is-enhanced-by-pd-1-checkpoint-blockade
#17
Martina Schmittnaegel, Nicolò Rigamonti, Ece Kadioglu, Antonino Cassará, Céline Wyser Rmili, Anna Kiialainen, Yvonne Kienast, Hans-Joachim Mueller, Chia-Huey Ooi, Damya Laoui, Michele De Palma
Pathological angiogenesis is a hallmark of cancer and a therapeutic target. Vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2; also known as ANG2) are proangiogenic cytokines that sustain tumor angiogenesis and limit antitumor immunity. We show that combined ANGPT2 and VEGFA blockade by a bispecific antibody (A2V) provided superior therapeutic benefits, as compared to the single agents, in both genetically engineered and transplant tumor models, including metastatic breast cancer (MMTV-PyMT), pancreatic neuroendocrine tumor (RIP1-Tag2), and melanoma...
April 12, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28402953/mechanisms-of-pd-1-pd-l1-expression-and-prognostic-relevance-in-non-hodgkin-lymphoma-a-summary-of-immunohistochemical-studies
#18
REVIEW
Pauline Gravelle, Barbara Burroni, Sarah Péricart, Cédric Rossi, Christine Bezombes, Marie Tosolini, Diane Damotte, Pierre Brousset, Jean-Jacques Fournié, Camille Laurent
Immune checkpoint blockade therapeutics, notably antibodies targeting the programmed death 1 (PD-1) receptor and its PD-L1 and PD-L2 ligands, are currently revolutionizing the treatment of cancer. For a sizeable fraction of patients with melanoma, lung, kidney and several other solid cancers, monoclonal antibodies that neutralize the interactions of the PD-1/PD-L1 complex allow the reconstitution of long-lasting antitumor immunity. In hematological malignancies this novel therapeutic strategy is far less documented, although promising clinical responses have been seen in refractory and relapsed Hodgkin lymphoma patients...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28401653/selective-blockade-of-b7-h3-enhances-antitumour-immune-activity-by-reducing-immature-myeloid-cells-in-head-and-neck-squamous-cell-carcinoma
#19
Liang Mao, Teng-Fei Fan, Lei Wu, Guang-Tao Yu, Wei-Wei Deng, Lei Chen, Lin-Lin Bu, Si-Rui Ma, Bing Liu, Yansong Bian, Ashok B Kulkarni, Wen-Feng Zhang, Zhi-Jun Sun
Immature myeloid cells including myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) promote tumour growth and metastasis by facilitating tumour transformation and angiogenesis, as well as by suppressing antitumour effector immune responses. Therefore, strategies designed to reduce MDSCs and TAMs accumulation and their activities are potentially valuable therapeutic goals. In this study, we show that negative immune checkpoint molecule B7-H3 is significantly overexpressed in human head and neck squamous cell carcinoma (HNSCC) specimen as compared with normal oral mucosa...
April 11, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28401381/antiangiogenic-therapy-combined-with-immune-checkpoint-blockade-in-renal-cancer
#20
REVIEW
Teele Kuusk, Laurence Albiges, Bernard Escudier, Nikolaos Grivas, John Haanen, Thomas Powles, Axel Bex
Antiangiogenic therapy with vascular endothelial growth factor (VEGF) inhibitors is the current first-line treatment in metastatic renal cell carcinoma (mRCC). Immunotherapy with checkpoint inhibitor has been recently added to the armamentarium of mRCC treatment. These therapies are based on treatment with antibodies that block programmed cell death-1 (PD-1), programmed cell death ligand 1 (PD-L1) pathways, demonstrating impressive response rates and improved survival in several tumour types. So far, nivolumab is the only approved anti-PD-1 monoclonal antibody after VEGF therapy in mRCC...
April 11, 2017: Angiogenesis
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