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Cancer Immunology Research

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https://www.readbyqxmd.com/read/29217732/peptide-blocking-of-pd-1-pd-l1-interaction-for-cancer-immunotherapy
#1
Chunlin Li, Nengpan Zhang, Jundong Zhou, Chen Ding, Yaqing Jin, Xueyuan Cui, Kefeng Pu, Yimin Zhu
Immunotherapy has become a promising alternative therapeutic approach for cancer patients. Interruption of immune checkpoints, such as CTLA-4 and PD-1, has been verified to be a successful means for cancer therapy in clinical trials. Monoclonal antibody (mAb) targeting to PD-L1 has been approved to treat urothelial carcinoma, non-small cell lung cancer or merkel cell carcinoma by the Food and Drug Administration (FDA). However, the high cost of the antibody can limit its application. In our study, TPP-1 (targeting PD-L1 peptide), which specifically binds to PD-L1 with high affinity, was identified through bacterial surface display methods...
December 7, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29208646/a-serum-protein-signature-associated-with-outcome-after-anti-pd1-therapy-in-metastatic-melanoma
#2
Mario Sznol, Ryan J Sullivan, Shauna Blackmon, Genevieve Boland, Harriet M Kluger, Ruth Halaban, Antonella Bacchiocchi, Paolo A Ascierto, Marilena Capone, Carlos Oliveira, Krista Meyer, Julia Grigorieva, Senait G Asmellash, Joanna Roder, Heinrich Roder, Jeffrey S Weber
A mass spectrometry analysis was performed using serum from patients receiving checkpoint inhibitors to define baseline protein signatures associated with outcome in metastatic melanoma. Pre-treatment serum was obtained from a development set of 119 melanoma patients on a trial of nivolumab with or without a multi-peptide vaccine and from patients receiving pembrolizumab, nivolumab, ipilimumab, or both nivolumab and ipilimumab. Spectra were obtained using matrix assisted laser desorption/ionization time of flight mass spectrometry...
December 5, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29187357/iap-antagonists-enhance-cytokine-production-from-mouse-and-human-inkt-cells
#3
Eleanor Clancy-Thompson, Lestat Ali, Patrick T Bruck, Mark A Exley, Richard S Blumberg, Glenn Dranoff, Michael Dougan, Stephanie K Dougan
Inhibitor of apoptosis protein (IAP) antagonists are in clinical trials for a variety of cancers, and mouse models show synergism between IAP antagonists and anti-PD-1 immunotherapy. Although IAP antagonists affect the intrinsic signaling of tumor cells, their most pronounced effects are on immune cells and the generation of antitumor immunity. Here we examined the effects of IAP antagonism on T-cell development using mouse fetal thymic organ culture and observed a selective loss of iNKT cells, an effector cell type of potential importance for cancer immunotherapy...
November 29, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29180536/high-affinity-gd2-specific-car-t-cells-induce-fatal-encephalitis-in-a-preclinical-neuroblastoma-model
#4
Sarah A Richman, Selene Nunez-Cruz, Babak Moghimi, Lucy Z Li, Zachary T Gershenson, Zissimos Mourelatos, David M Barrett, Stephan A Grupp, Michael C Milone
The GD2 ganglioside, which is abundant on the surface of neuroblastoma cells, is targeted by an FDA-approved therapeutic monoclonal antibody and is an attractive tumor-associated antigen for cellular immunotherapy. Chimeric antigen receptor (CAR)-modified T cells can have potent antitumor activity in B-cell malignancies, and trials to harness this cytolytic activity toward GD2 in neuroblastoma are underway. In an effort to enhance the antitumor activity of CAR T cells that target GD2, we generated variant CAR constructs predicted to improve the stability and the affinity of the GD2-binding, 14G2a-based, single-chain variable fragment (scFv) of the CAR, and compared their properties in vivo...
November 27, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29180535/radiotherapy-and-ctla-4-blockade-shape-the-tcr-repertoire-of-tumor-infiltrating-t-cells
#5
Nils-Petter Rudqvist, Karsten A Pilones, Claire Lhuillier, Erik Wennerberg, John-William Sidhom, Ryan O Emerson, Harlan S Robins, Jonathan Schneck, Silvia C Formenti, Sandra Demaria
Immune checkpoint inhibitors activate T cells to reject tumors. Unique tumor mutations are key T-cell targets, but a comprehensive understanding of the nature of a successful antitumor T-cell response is lacking. To investigate the T-cell receptor (TCR) repertoire associated with treatment success versus failure we used a well-characterized mouse carcinoma that is rejected by CD8 T cells in mice treated with radiotherapy (RT) and anti-CTLA-4 in combination, but not as monotherapy, and comprehensively analyzed tumor-infiltrating lymphocytes (TILs) by high-throughput sequencing of the TCRΒ CDR3 region...
November 27, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29146881/beta-adrenergic-signaling-impairs-anti-tumor-cd8-t-cell-responses-to-b-cell-lymphoma-immunotherapy
#6
Michael D Nissen, Erica K Sloan, Stephen R Mattarollo
Beta-adrenergic receptor (betaAR) signaling regulates many physiological processes, including immune system responses. There is growing evidence also for betaAR-induced modulation of cancer growth and metastasis. In the Eu-myc mouse model of B-cell lymphoma, we investigated the effects of chronically elevated betaAR signaling on lymphoma progression and anti-tumor immunity, as well as the impact on cancer immunotherapy. Chronic treatment with the non-selective beta-agonist isoprenaline promoted lymphoma development in a manner dependent on signaling within the hematopoietic compartment...
November 16, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29141981/impact-of-tumor-purity-on-immune-gene-expression-and-clustering-analyses-across-multiple-cancer-types
#7
Je-Keun Rhee, Yu Chae Jung, Kyu Ryung Kim, Jinseon Yoo, Jeeyoon Kim, Yong-Jae Lee, Yoon Ho Ko, Han Hong Lee, Byoung Chul Cho, Tae-Min Kim
Surgical archives of tumor specimens are often impure. The presence of RNA transcripts from nontumor cells, such as immune and stromal cells, can impede analyses of cancer expression profiles. To systematically analyze the impact of tumor purity, the gene expression profiles and tumor purities were obtained for 7794 tumor specimens across 21 tumor types (available in the Cancer Genome Atlas consortium). First, we observed that genes with roles in immunity and oxidative phosphorylation were significantly inversely correlated and correlated with the tumor purity, respectively...
November 15, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29133290/cd137-4-1bb-costimulation-modifies-dna-methylation-in-cd8-t-cell-relevant-genes
#8
M Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Carmen Molina, Saray Garasa, Arantza Azpilicueta, Inaki Etxeberria, Alfonso R Sanchez-Paulete, Alan J Korman, Manel Esteller, Juan Sandoval, Ignacio Melero
CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA-methylation arrays were carried out on human peripheral blood CD8+ T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors...
November 13, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29122838/soluble-cd80-protein-delays-tumor-growth-and-promotes-tumor-infiltrating-lymphocytes
#9
Lucas A Horn, Tiha M Long, Ryan Atkinson, Virginia Clements, Suzanne Ostrand-Rosenberg
Tumor cells employ various immune suppressive strategies to overcome antitumor immunity. One such method is tumor expression of programmed death ligand-1 (PD-L1), which triggers apoptotic death or anergy upon binding programmed death-1 (PD-1) on T cells. Our previous in vitro cellular studies with human and mouse PD-L1+ tumor cells demonstrated that a soluble form of the costimulatory molecule CD80 prevented PD-L1-mediated immune suppression and restored T-cell activation by binding PD-L1 and blocking interaction with PD-1...
November 9, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29109077/safety-and-efficacy-of-intratumoral-injections-of-chimeric-antigen-receptor-car-t-cells-in-metastatic-breast-cancer
#10
Julia Tchou, Yangbing Zhao, Bruce L Levine, Paul J Zhang, Megan M Davis, Jan Joseph Melenhorst, Irina Kulikovskaya, Andrea L Brennan, Xiajun Liu, Simon F Lacey, Avery Posey, Austin D Williams, Alycia So, Jose R Conejo-Garcia, Gabriela Plesa, Regina M Young, Shannon McGettigan, Jean Campbell, Robert H Pierce, Jennifer M Matro, Angela M DeMichele, Amy S Clark, Laurence J N Cooper, Lynn M Schuchter, Robert H Vonderheide, Carl H June
Chimeric antigen receptors (CARs) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ~50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602)...
November 6, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29097422/intratumoral-cd8-t-cell-apoptosis-is-a-major-component-of-t-cell-dysfunction-and-impedes-anti-tumor-immunity
#11
Brendan L Horton, Jason B Williams, Alexandra Cabanov, Stefani Spranger, Thomas F Gajewski
Subsets of human tumors are infiltrated with tumor antigen-specific CD8(+) T cells (TILs) despite tumor progression. These TILs are thought to be inactivated by the immunosuppressive tumor microenvironment, through the engagement of inhibitory receptors such as CTLA-4 and PD-1. However, antigen-specific CD8+ TILs are not functionally inert, but are undergoing activation in situ. Here, we show that antigen-specific CD8(+) TIL are actively proliferating, yet also undergo high rates of apoptosis, leading to a vicious cycle of activation and death that limits immune efficacy...
November 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29097421/cisplatin-alters-antitumor-immunity-and-synergizes-with-pd-1-pd-l1-inhibition-in-head-and-neck-squamous-cell-carcinoma
#12
Linda Tran, Clint T Allen, Roy Xiao, Ellen Moore, Ruth Davis, So-Jin Park, Katie Spielbauer, Carter Van Waes, Nicole C Schmitt
Head and neck squamous cell carcinoma (HNSCC) has been treated for decades with cisplatin chemotherapy, and anti-PD-1 immunotherapy has recently been approved for the treatment of this disease. However, preclinical studies of how antitumor immunity in HNSCC is affected by cisplatin alone or in combination with immunotherapies are lacking. Here, we show that sublethal doses of cisplatin may enhance antigen presentation and T-cell killing in vitro, though cisplatin also upregulates tumor cell expression of PD-L1 and may impair T-cell function at higher doses...
November 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29097420/combination-of-cd40-agonism-and-csf-1r-blockade-reconditions-tumor-associated-macrophages-and-drives-potent-antitumor-immunity
#13
Karla R Wiehagen, Natasha M Girgis, Douglas H Yamada, Andressa A Smith, Szeman Ruby Chan, Iqbal S Grewal, Michael Quigley, Raluca I Verona
Efficacious antitumor immune responses must overcome multiple suppressive mechanisms in the tumor microenvironment to control cancer progression. In this study, we demonstrate that dual targeting of suppressive myeloid populations by inhibiting CSF-1/CSF-1R signaling and activation of antigen-presenting cells with agonist anti-CD40 treatment confers superior antitumor efficacy and increased survival compared with monotherapy treatment in preclinical tumor models. Concurrent CSF-1R blockade and CD40 agonism lead to profound changes in the composition of immune infiltrates, causing an overall decrease in immunosuppressive cells and a shift toward a more inflammatory milieu...
November 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29097419/differential-expression-of-homing-receptor-ligands-on-tumor-associated-vasculature-that-control-cd8-effector-t-cell-entry
#14
Amber N Woods, Ashley L Wilson, Nithya Srivinisan, Jianhao Zeng, Arun B Dutta, J David Peske, Eric F Tewalt, Randal K Gregg, Andrew R Ferguson, Victor H Engelhard
Although CD8+ T cells are critical for controlling tumors, how they are recruited and home to primary and metastatic lesions is incompletely understood. We characterized the homing receptor (HR) ligands on tumor vasculature to determine what drives their expression and their role in T cell entry. The anatomic location of B16-OVA tumors affected the expression of E-selectin, MadCAM-1, and VCAM-1, whereas the HR ligands CXCL9 and ICAM-1 were expressed on the vasculature regardless of location. VCAM-1 and CXCL9 expression was induced by IFNgamma-secreting adaptive immune cells...
November 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29079655/reversible-transgene-expression-reduces-fratricide-and-permits-4-1bb-costimulation-of-car-t-cells-directed-to-t-cell-malignancies
#15
Maksim Mamonkin, Malini Mukherjee, Madhuwanti Srinivasan, Sandhya Sharma, Diogo Gomes-Silva, Feiyan Mo, Giedre Krenciute, Jordan S Orange, Malcolm K Brenner
T cells expressing second-generation chimeric antigen receptors (CARs) specific for CD5, a T-cell surface marker present on normal and malignant T cells, can selectively kill tumor cells. We aimed to improve this killing by substituting the CD28 costimulatory endodomain (28.z) with 4-1BB (BB.z), as 28.z CD5 CAR T cells rapidly differentiated into short-lived effector cells. In contrast, 4-1BB costimulation is known to promote development of the central memory subpopulation. Here, we found BB.z CD5 CAR T cells had impaired growth compared to 28...
October 27, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29079654/characterization-of-thyroid-disorders-in-patients-receiving-immune-checkpoint-inhibition-therapy
#16
Hyunju Lee, F Stephen Hodi, Anita Giobbie-Hurder, Patrick A Ott, Elizabeth I Buchbinder, Rizwan Haq, Sara Tolaney, Romualdo Barroso-Sousa, Kevin Zhang, Hilary Donahue, Meredith Davis, Maria E Gargano, Kristina M Kelley, Rona S Carroll, Ursula B Kaiser, Le Min
Thyroid disorders have emerged as one of the most common immune-related adverse events associated with anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 therapy. This study characterizes and compares the evolution of monotherapy and combination therapy-related thyroid disorders. We analyzed the dynamic evolution of thyroid disorders in 45 patients who developed thyroid disorders following treatment with either anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination therapy. The patients presented with thyrotoxicosis or hypothyroidism as the initial presentation of their thyroid disorder...
October 27, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29070650/interleukin-12-from-cd103-batf3-dependent-dendritic-cells-required-for-nk-cell-suppression-of-metastasis
#17
Deepak Mittal, Dipti Vijayan, Eva M Putz, Amelia R Aguilera, Kate A Markey, Jasmin Straube, Stephen Kazakoff, Stephen L Nutt, Kazuyoshi Takeda, Geoffrey R Hill, Nicola Waddell, Mark J Smyth
Several host factors may affect the spread of cancer to distant organs, however the intrinsic role of dendritic cells (DCs) in controlling metastasis is poorly described. Here we show in several tumor models that although the growth of primary tumors in Batf3-deficient mice, which lack cross-presenting DCs, was not different from primary tumors in wild-type (WT) control mice, Batf-deficient mice had increased experimental and spontaneous metastasis and poorer survival. The increased metastasis was independent of CD4+ and CD8+ T lymphocytes, but required NK cells and IFNγ...
October 25, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29070649/complex-immune-evasion-strategies-in-classical-hodgkin-lymphoma
#18
Frederik Wein, Marc A Weniger, Benedikt Höing, Judith C Arnolds, Andreas Hüttmann, Martin-Leo Hansmann, Sylvia Hartmann, Ralf Küppers
The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only about 1% Hodgkin and Reed/Sternberg (HRS) tumor cells. T cells are usually the largest population of cells in the cHL microenvironment, encompassing T helper (Th) cells, regulatory T (Treg) cells and cytotoxic T cells. Th and Treg cells presumably provide essential survival signals for HRS cells. Treg cells are also involved in rescuing HRS cells from anti-tumor immune responses...
October 25, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29054890/natural-killer-t-cell-immunotherapy-in-combination-with-chemotherapy-induced-immunogenic-cell-death-targets-metastatic-breast-cancer
#19
Simon Gebremeskel, Lynnea Lobert, Kaitlyn Tanner, Brynn Walker, Tora Oliphant, Livia E Clarke, Graham Dellaire, Brent Johnston
Natural killer T (NKT) cells are glycolipid-reactive lymphocytes that promote cancer control. In previous studies, NKT-cell activation improved survival and antitumor immunity in a post-surgical mouse model of metastatic breast cancer. Herein, we investigated whether NKT-cell activation could be combined with chemotherapeutic agents to augment therapeutic outcomes. Gemcitabine and cyclophosphamide analogs enhanced the potential immunogenicity of 4T1 mammary carcinoma cells by increasing the expression of antigen-presenting molecules (MHC-I, MHC-II, and CD1d) and promoting exposure or release of immunogenic cell death markers (calreticulin, HMGB1 and ATP)...
October 20, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29051161/prostate-cancer-cells-express-more-androgen-receptor-ar-following-androgen-deprivation-improving-recognition-by-ar-specific-t-cells
#20
Brian M Olson, Melissa Gamat, Joseph Seliski, Thomas Sawicki, Justin Jeffery, Leigh Ellis, Charles G Drake, Jamey Weichert, Douglas G McNeel
Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anticancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR...
October 19, 2017: Cancer Immunology Research
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