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Mohsen Abdolmaleki, Nazanin Mojtabavi, Mahdi Zavvar, Mohammad Vaezi, Farshid Noorbakhsh, Mohammad Hossein Nicknam
T cell exhaustion is an immunosuppressive mechanism which occurs in chronic viral infections, solid tumors and hematologic malignancies. Exhausted T cell has increased the expression of inhibitory receptors, and functional impairment. In this study, we investigated the expression from some of those inhibitory receptors being Programmed death 1 (PD-1), T cell immunoglobulin and mucin domain containing molecules 3 (TIM-3) and CD244 on T cells from Iranian acute myeloid leukemia (AML) patients. Peripheral blood samples were collected from Iranian newly diagnosed AML patients and flow cytometric analysis was accomplished for cell surface expression of PD-1, TIM-3, and CD244 on T lymphocytes...
June 2018: Iranian Journal of Allergy, Asthma, and Immunology
Graham Pawelec
Immunosenescence might be expected to reduce the efficacy of checkpoint blockade, which depends on a functionally intact immune system. However, it seems that older melanoma patients may respond better to anti-PD1 treatment than younger patients, possibly due to their having fewer regulatory T-cells relative to CD8+ T-cells within tumour deposits.
June 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Claus Wittekindt, Steffen Wagner, Shachi Jenny Sharma, Nora Würdemann, Jennifer Knuth, Henrike Reder, Jens Peter Klußmann
Head and neck cancer is the sixth most common cancer with over 500000 annually reported incident cases worldwide. Besides major risk factors tobacco and alcohol, oropharyngeal squamous cell carcinomas (OSCC) show increased association with human papillomavirus (HPV). HPV-associated and HPV-negative OSCC are 2 different entities regarding biological characteristics, therapeutic response, and patient prognosis. In HPV OSCC, viral oncoprotein activity, as well as genetic (mutations and chromosomal aberrations) and epigenetic alterations plays a key role during carcinogenesis...
March 2018: Laryngo- Rhino- Otologie
Patrick A Mayes, Kenneth W Hance, Axel Hoos
Immune cell functions are regulated by co-inhibitory and co-stimulatory receptors. The first two generations of cancer immunotherapy agents consist primarily of antagonist antibodies that block negative immune checkpoints, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte protein 4 (CTLA4). Looking ahead, there is substantial promise in targeting co-stimulatory receptors with agonist antibodies, and a growing number of these agents are making their way through various stages of development...
June 15, 2018: Nature Reviews. Drug Discovery
Curtis H Kugel, Stephen M Douglass, Marie R Webster, Amanpreet Kaur, Qin Liu, Xiangfan Yin, Sarah A Weiss, Farbod Darvishian, Rami N Al-Rohil, Abibatou Ndoye, Reeti Behera, Gretchen M Alicea, Brett L Ecker, Mitchell Fane, Michael J Allegrezza, Nikolaos Svoronos, Vinit Kumar, Daniel Y Wang, Rajasekharan Somasundaram, Siwen Hu-Lieskovan, Alpaslan Ozgun, Meenhard Herlyn, Jose R Conejo-Garcia, Dmitry Gabrilovich, Erica L Stone, Theodore S Nowicki, Jeffrey Sosman, Rajat Rai, Matteo S Carlino, Georgina V Long, Richard Marais, Antoni Ribas, Zeynep Eroglu, Michael A Davies, Bastian Schilling, Dirk Schadendorf, Wei Xu, Ravi K Amaravadi, Alexander M Menzies, Jennifer L McQuade, Douglas B Johnson, Iman Osman, Ashani T Weeraratna
Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1. Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies. Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy...
June 13, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Cristiane R Ferreira, Shuchun Zhao, Malaya K Sahoo, Benjamin Pinsky, Jenna Weber, Luis A P C Lage, Juliana Pereira, Maria C N Zerbini, Yasodha Natkunam
Forkhead box P3 (FOXP3) is a specific marker for regulatory T-cells (Tregs). We report 6 cases of T-cell lymphomas with Treg phenotype based on diffuse positivity for FOXP3 in tumor cells. The patients showed a median age of 56years with a male predominance. Sites of disease included lymph nodes (4), skin (2), subcutaneous tissue (1) and bone marrow (1). All cases showed monomorphic large cells, some with Hodgkin-like or anaplastic cells. All cases expressed pan T cell markers and lacked cytotoxic markers; one case showed diffuse PD1 staining...
June 10, 2018: Human Pathology
Koji Kono, Kousaku Mimura, Reo Yamada, Daisuke Ujiie, Suguru Hayase, Takeshi Tada, Hiroyuki Hanayama, Aung Kyi Thar Min, Masahiko Shibata, Tomoyuki Momma, Zenichirou Saze, Shinji Ohki
BACKGROUND: Immunotherapy has become a promising treatment strategy for cancer. Immune checkpoint blockade with anti-CTLA4 mAb and anti-PD-1 mAb has demonstrated clear evidence of objective responses including improved overall survival and tumor shrinkage, driving renewed enthusiasm for cancer immunotherapy in multiple cancer types including esophageal squamous cell carcinoma (ESCC). There are several clinical trials using anti-PD1 mAb for ESCC in early phases and the results are currently promising...
January 2018: Esophagus: Official Journal of the Japan Esophageal Society
Yue Wang, Xiaokai Zhang, Liangliang Yang, Jinru Xue, Guangrui Hu
Myeloid derived suppressor cells (MDSC) play a pivotal role in tumor immune evasion and MDSC levels increased in patients with cancer. Studies confirmed the associations between MDSC and various cytokines in the peripheral blood. However, little is known about the association between parenchymal MDSC subsets and cytokines, or the mechanism drawing MDSC into tumor parenchyma. This study was to analyze the correlation between MDSC subsets and CCL2 level in lung cancer model. G-MDSC and M-MDSC from the blood and parenchyma were analyzed by flow cytometry and western blot in the lung tumor model...
June 2018: Journal of Bone Oncology
Barbacki Ariane, Peter G Maliha, Marie Hudson, David Small
Immune checkpoint inhibitors have revolutionized cancer therapy. Given their mechanism of action, immune-related adverse events have been associated with their use. We present the first documented case of pembrolizumab-induced grade IV neutropenia. A 73-year-old women known for myositis, Crohn's disease, and hypothyroidism and diagnosed with PD-L1 positive stage IV pulmonary adenocarcinoma is treated with Pembrolizumab. She develops grade IV neutropenia 2 weeks after her second infusion. She is therefore hospitalized and treated initially with corticosteroids, granulocyte colony-stimulating factor, and intravenous immunoglobulins...
June 8, 2018: Anti-cancer Drugs
Cédric Rossi, Julia Gilhodes, Marie Maerevoet, Charles Herbaux, Franck Morschhauser, Pauline Brice, Sylvain Garciaz, Cécile Borel, Loïc Ysebaert, Lucie Obéric, Julien Lazarovici, Bénédicte Deau, Jehan Dupuis, Adrien Chauchet, Julie Abraham, Fontanet Bijou, Aspasia Stamatoullas-Bastard, Jean-Valère Malfuson, Camille Golfier, Camille Laurent, Sarah Pericart, Alexandra Traverse-Glehen, Salim Kanoun, Thomas Filleron, René-Olivier Casasnovas, Hervé Ghesquières
Anti-PD-1 therapy provides high response rates in Hodgkin lymphoma (HL) patients who have relapsed or are refractory (R/R) to autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV), but median progression free survival (PFS) is only one year. The efficacy of treatment following anti-PD-1 is not well known. We retrospectively investigated the efficacy of salvage therapies for unsatisfactory response to anti-PD-1 therapy, assessed by PET-CT according to the Lugano criteria, in 30 R/R HL patients...
June 8, 2018: American Journal of Hematology
Karl A Brokstad, Marita Fredriksen, Fan Zhou, Brith Bergum, Johan G Brun, Rebecca J Cox, Kathrine Skarstein
Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by exocrine gland dysfunction, mainly causing sicca symptoms. B cells have a prominent role in SS, and the T follicular helper (TFH ) cells provide B cells with survival- and specialization signals in germinal centers. Here we investigate peripheral TFH cells in pSS. Sixteen pSS patients and healthy controls were enrolled in the study, with thirteen women and three men in each group. Whole blood was collected and separated into PBMC and plasma, followed by cryopreservation...
June 8, 2018: Scandinavian Journal of Immunology
Koichi Ohshima, Hiroaki Miyoshi, Kyohei Yamada
Angioimmunoblastic T-cell lymphoma (AITL) originates from follicular helper T cells and shows variable biological and clinical presentations. The survival rate of patients with AITL did not correlate with T-cell clonality, the presence of EBV-infected cells, EBV-DNA copy number, or IgH rearrangements. However, tumor-associated macrophage/M2 macrophages significantly correlated with worse overall survival (OS). Additionally, patients with composite lymphoma with diffuse large B cell lymphoma and AITL showed worse OS...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Yi Fan, Joseph G Naglich, Jennifer D Koenitzer, Humberto Ribeiro, Jonathan Lippy, Jordan Blum, Xin Li, Christina Milburn, Bryan Barnhart, Litao Zhang, Mark P Fereshteh
Enhancing antitumor activities of the human immune system is a clinically proven approach with the advent of monoclonal antibodies recognizing programmed cell death protein-1 (PD1) receptors on immune cell surfaces. Historically, using flow cytometry as a means to assess next-generation agent activities was underused, largely due to limits on cell number and assay sensitivity. Here, we leveraged an IntelliCyt high-throughput flow cytometry platform to monitor human dendritic cell maturation and lymphocyte proliferation in mixed lymphocyte reactions...
May 1, 2018: SLAS Discovery
Elizabeth Ahern, Heidi Harjunpää, Jake S O'Donnell, Stacey Allen, William C Dougall, Michele W L Teng, Mark J Smyth
Receptor activator of NF-κB ligand (RANKL) and its receptor RANK, are members of the tumor necrosis factor and receptor superfamilies, respectively. Antibodies targeting RANKL have recently been evaluated in combination with anti-CTLA4 in case reports of human melanoma and mouse models of cancer. However, the efficacy of anti-RANKL in combination with antibodies targeting other immune checkpoint receptors such as PD1 has not been reported. In this study, we demonstrated that blockade of RANKL improves anti-metastatic activity of antibodies targeting PD1/PD-L1 and improves subcutaneous growth suppression in mouse models of melanoma, prostate and colon cancer...
2018: Oncoimmunology
Edwin R Parra, Pamela Villalobos, Carmen Behrens, Mei Jiang, Apar Pataer, Stephen G Swisher, William N William, Jiexin Zhang, Jack Lee, Tina Cascone, John V Heymach, Marie-Andrée Forget, Cara Haymaker, Chantale Bernatchez, Neda Kalhor, Annikka Weissferdt, Cesar Moran, Jianjun Zhang, Ara Vaporciyan, Don L Gibbons, Boris Sepesi, Ignacio I Wistuba
BACKGROUND: The clinical efficacy observed with inhibitors of programed cell death 1/programed cell death ligand 1 (PD-L1/PD-1) in cancer therapy has prompted studies to characterize the immune response in several tumor types, including lung cancer. However, the immunological profile of non-small cell lung carcinoma (NSCLC) treated with neoadjuvant chemotherapy (NCT) is not yet fully characterized, and it may be therapeutically important. The aim of this retrospective study was to characterize and quantify PD-L1/PD-1 expression and tumor-associated immune cells (TAICs) in surgically resected NSCLCs from patients who received NCT or did not receive NCT (non-NCT)...
June 6, 2018: Journal for Immunotherapy of Cancer
Raíssa Fonseca, Rafael Moysés Salgado, Henrique Borges da Silva, Rogério Silva do Nascimento, Maria Regina D'Império-Lima, José Maria Alvarez
Chagas disease is a neglected parasitic infection that affects around six to seven million people, mainly in Latin America. About 30-35% of infected people present chronic Chagas cardiomyopathy (CCC), which eventually leads to death. This condition is characterized by local parasite persistence and leukocyte infiltration. In a murine model of CCC, we observed that among infiltrating leukocytes, CD4+ and CD8+ T cells were in higher frequency in the heart of chronically infected mice, although elevated expression of the regulatory molecules programmed cell death protein 1 (PD1) and PDL1 suggested these cells could be inhibited...
2018: Frontiers in Immunology
Guillaume Herbreteau, Audrey Vallée, Anne-Chantal Knol, Sandrine Théoleyre, Gaelle Quéreux, Emilie Varey, Amir Khammari, Brigitte Dréno, Marc G Denis
Immunotherapies have changed the medical management of metastatic melanoma. However, the early detection of patients who do not respond to these treatments is a key issue. We evaluated the quantitative monitoring of circulating tumor DNA (ctDNA) as an early predictor of response to anti-PD1. Patients treated with anti-PD1 for metastatic mutated melanoma were selected. The somatic alteration detected on the tumor tissue was quantified on plasma DNA by digital PCR (dPCR) at treatment initiation, after 2 and 4 weeks of treatment, and then every 4 weeks until progression...
May 18, 2018: Oncotarget
Magdalena Witkowska, Piotr Smolewski
Genetic and/or epigenetic changes provide antigen-derived diversity in neoplastic cells. Beside, these cells do not initiate immune response of host organisms. A variety of factors are responsible for the resistant to treatment, including individual variations in patients and somatic cell genetic differences in tumors, even those from the same tissue of origin. Immune system is controlled by several controlling mechanisms. Recently, a significant progress in hematologic treatment has been made; however, majority of diseases still remain incurable...
2018: Journal of Immunology Research
Marie-Andrée Forget, Cara Haymaker, Kenneth R Hess, Yuzhong Jeff Meng, Caitlin Creasy, Tatiana V Karpinets, Orenthial J Fulbright, Jason Roszik, Scott E Woodman, Young Uk Kim, Donastas Sakellariou-Thompson, Ankit Bhatta, Arely Wahl, Esteban Flores, Shawne T Thorsen, Rene J Tavera, Renjith Ramachandran, Audrey M Gonzalez, Christopher Toth, Seth Wardell, Rahmatu Mansaray, Vruti Patel, Destiny Joy Carpio, Carol S Vaughn, Chantell M Farinas, Portia G Velasquez, Wen-Jen Hwu, Sapna P Patel, Michael A Davies, Adi Diab, Isabella C Glitza, Hussein Tawbi, Michael K K Wong, Suzanne Cain, Merrick I Ross, Jeffrey E Lee, Jeffrey E Gershenwald, Anthony Lucci, Richard Royal, J N Cormier, Jennifer A Wargo, Laszlo G Radvanyi, Carlos A Torres Cabala, Rameen Beroukhim, Patrick Hwu, Rodabe N Amaria, Chantale Bernatchez
PURPOSE: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. EXPERIMENTAL DESIGN: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival and progression free survival...
May 30, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ronny Ben-Avi, Ronit Farhi, Alon Ben-Nun, Marina Gorodner, Eyal Greenberg, Gal Markel, Jacob Schachter, Orit Itzhaki, Michal J Besser
Adoptive cell therapy (ACT) of tumor infiltration lymphocytes (TIL) yields promising clinical results in metastatic melanoma patients, who failed standard treatments. Due to the fact that metastatic lung cancer has proven to be susceptible to immunotherapy and possesses a high mutation burden, which makes it responsive to T cell attack, we explored the feasibility of TIL ACT in non-small cell lung cancer (NSCLC) patients. Multiple TIL cultures were isolated from tumor specimens of five NSCLC patients undergoing thoracic surgery...
May 29, 2018: Cancer Immunology, Immunotherapy: CII
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