Haimei Zhou, Huamei He, Ruijing Liang, Hong Pan, Ze Chen, Guanjun Deng, Shengping Zhang, Yifan Ma, Lanlan Liu, Lintao Cai
Immunotherapy is one of the most promising approaches to inhibit tumor growth and metastasis by activating host immune functions. However, the arising problems such as low immune response caused by complex tumor microenvironment and extremely systemic immune storm still limit the clinical applications of immunotherapy. Here, we construct Poly I: C-encapsulated poly (lactic-co-glycolic acid) nanoparticles (PLP NPs) with a slow release profile. A biomimetic system (MPLP), which loads PLP NPs on the surface of bone marrow-derived macrophage (BMDM) via the maleimide-thiol conjugation, is synthesized to effectively deliver PLP, control drug release and activate the tumor-specific immune response in situ...
January 7, 2021: Biomaterials
M Angeles Montero, Ozan Aricak, Lorand Kis, Akira Yoshikawa, Luigi De Petris, Oscar Grundberg, Hoa H N Pham, Anja C Roden, Junya Fukuoka, Richard Attanoos, Ricardo Guijarro, Felix Alarcón, Kati Lindström, Cristian Ortiz-Villalón
INTRODUCTION: PD1/PD-L1 pathway targeting therapies are nowadays an established treatment option for patients with NSCLC. We assessed whether PD-L1 expression in NSCLC tumor cells was associated with specific clinical features or overall survival using four different clones. METHODS AND RESULTS: A retrospective study included formalin-fixed paraffin embedded (FFPE) surgical tumors from 482 patients. PD-L1 status was assessed with immunohistochemistry in tumor cells on tissue microarrays using clones 28-8, 22C3, SP263 and SP142...
January 9, 2021: Annals of Diagnostic Pathology
Fan Zou, Jizhou Tan, Ting Liu, Bingfeng Liu, Yaping Tang, Hui Zhang, Jiaping Li
CD39, expressed by tumor infiltrating lymphocytes (TILs), is a marker to identify tumor-reactive T cells, which is frequently associated with stronger anti-tumor activity than bystander T cells in a variety of malignancies. Therefore, CD39 could be a promising marker for identifying the active anti-tumor immune cells used for cellular immunotherapy. To test this possibility, we constructed the hepatitis B virus surface protein (HBVs)-specific chimeric antigen receptor T-cells (HBVs-CAR-T cells) and generated the personalized tumor-reactive CD8+ T cells...
January 20, 2021: Molecular Therapy
Cameron MacDonald, Samuel Ministero, Manu Pandey, Denisha Robinson, Evan Forti Hong, Bonnie Hylander, Philip McCarthy, Christopher Gordon, Elizabeth Repasky, Hemn Mohammadpour
Myeloid derived suppressor cells (MDSCs) are a diverse collection of immune cells that suppress anti-tumor immune responses. Decreasing MDSCs accumulation in the tumor microenvironment could improve the anti-tumor immune response and improve immunotherapy. Here, we examine the impact of physiologically relevant thermal treatments on the accumulation of MDSCs in tumors in mice. We found that different temperature-based protocols, including 1) weekly whole-body hyperthermia, 2) housing mice at their thermoneutral temperature (TT, ~30 °C), and 3) housing mice at a subthermoneutral temperature (ST,~22 °C) while providing a localized heat source, each resulted in a reduction in MDSC accumulation and improved tumor growth control compared to control mice housed at ST, which is the standard, mandated housing temperature for laboratory mice...
January 9, 2021: Cellular Immunology
Iris Kamer, Elizabeta Bab-Dinitz, Oranit Zadok, Efrat Ofek, Teodor Gottfried, Inbal Daniel-Meshulam, Goni Hout-Siloni, Alon Ben Nun, Iris Barshack, Amir Onn, Jair Bar
One of the major hurdles for the advancement of cancer immunotherapy is lack of robust, accessible experimental models. We aimed to produce an ex-vivo organ culture (EVOC) model of immunotherapy for non-small cell lung cancer (NSCLC). Freshly resected early stage tumors were collected from the operating room, fragmented to clusters < 450 µm and cultured with fetal calf serum and human autologous serum. The resulting EVOC includes cancer epithelial cells within tumor tissue clusters and immune cells...
January 23, 2021: Cancer Immunology, Immunotherapy: CII
Yosuke Yoshida, Masayuki Kaneko, Mamoru Narukawa
BACKGROUND: Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) in patients with advanced non-small cell lung cancer. OBJECTIVE: This study aimed to investigate an impact of advantage in tumor response on the correlation between PFS and OS in advanced non-small cell lung cancer. METHODS: Based on a literature search, we identified randomized controlled trials of first-line therapy for advanced non-small cell lung cancer...
January 23, 2021: Pharmaceutical Medicine
Shalu Sharma Kharkwal, Christopher T Johndrow, Natacha Veerapen, Himanshu Kharkwal, Noemi A Saavedra-Avila, Leandro J Carreño, Samantha Rothberg, Jinghang Zhang, Scott J Garforth, Peter J Jervis, Lianjun Zhang, Alena Donda, Amareeta K Besra, Liam R Cox, Steven C Almo, Alan Howell, Elizabeth E Evans, Maurice Zauderer, Gurdyal S Besra, Steven A Porcelli
CD1d-restricted invariant natural killer T cells (iNKT cells) mediate strong anti-tumor immunity when stimulated by glycolipid agonists. However, attempts to develop effective iNKT cell agonists for clinical applications have been thwarted by potential problems with dose-limiting toxicity and by activation-induced iNKT cell anergy, which limits the efficacy of repeated administration. To overcome these issues, we developed a unique bispecific T cell engager (BiTE) based on covalent conjugates of soluble CD1d with photoreactive analogs of the glycolipid α-galactosylceramide...
January 22, 2021: Cancer Research
Marcus P Kelly, Sosina Makonnen, Carlos Hickey, T Cody Arnold, Jason T Giurleo, Richard Tavaré, Makenzie Danton, Christian Granados, Ishita Chatterjee, Drew Dudgeon, Marc W Retter, Dangshe Ma, William C Olson, Gavin Thurston, Jessica R Kirshner
BACKGROUND: Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blocking antibodies including cemiplimab have generated profound clinical activity across diverse cancer types. Tumorous PD-L1 expression, as assessed by immunohistochemistry (IHC), is an accepted predictive marker of response to therapy in some cancers. However, expression is often dynamic and heterogeneous, and therefore not reliably captured by IHC from tumor biopsies or archival samples. Thus, there is significant need for accurate whole-body quantification of PD-L1 levels...
January 2021: Journal for Immunotherapy of Cancer
April A N Rose, Susan M Armstrong, David Hogg, Marcus O Butler, Samuel D Saibil, Diana P Arteaga, Thiago Pimentel Muniz, Deirdre Kelly, Danny Ghazarian, Ian King, Zaid Saeed Kamil, Kendra Ross, Anna Spreafico
PURPOSE: Anti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma. METHODS: We performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019...
January 2021: Journal for Immunotherapy of Cancer
Rajeev Masson, Gopi Manthripragada, Raymond Liu, Jahan Tavakoli, Kenny Mok
INTRODUCTION: Immune checkpoint inhibitors (ICI) have led to improved survival in patients with a number of different tumor types. The ICI agent nivolumab induces anti-tumor immune responses by inhibiting the programmed cell death 1 protein, but side effects include cardiac immune-related adverse events (irAE) such as myocarditis.¹ The association of nivolumab with atherosclerotic disease has been rarely reported. CASE PRESENTATION: A 62-year-old man with metastatic melanoma and recent myocardial infarction (MI) presented with recurrent MI after having undergone several cycles of nivolumab therapy...
December 2020: Permanente Journal
Hans-Georg Wirsching, Patrick Roth, Michael Weller
Glioblastoma is invariably deadly and is characterized by extensive vascularization and macrophage-dominant immunosuppression; nevertheless, anti-angiogenesis has so far failed to prolong overall survival of patients. Regardless of the problems in clinical development, the rationale for the application of anti-angiogenics in glioblastoma remains. Areas covered: Mechanisms of glioblastoma resistance to anti-angiogenic agents are discussed, including vessel co-option and amplification of hypoxic signaling in response to vessel destruction...
January 22, 2021: Expert Opinion on Therapeutic Targets
Michael I Koukourakis, Alexandra Giatromanolaki
INTRODUCTION: The immune response has been recognized as a major tumor-eradication component of radiotherapy. OBJECTIVE: This review studies, under a clinical perspective, two contrasting effects of radiotherapy, namely immunosuppression and radiovaccination. MATERIALS AND METHODS: We critically reviewed the available clinical and experimental experience on radiotherapy-induced lymphopenia. RESULTS: Radiation-induced tumor damage promotes radio-vaccination, enhances cytotoxic immune responses, and potentiates immunotherapy...
January 19, 2021: Critical Reviews in Oncology/hematology
Carl M Gay, C Allison Stewart, Elizabeth M Park, Lixia Diao, Sarah M Groves, Simon Heeke, Barzin Y Nabet, Junya Fujimoto, Luisa M Solis, Wei Lu, Yuanxin Xi, Robert J Cardnell, Qi Wang, Giulia Fabbri, Kasey R Cargill, Natalie I Vokes, Kavya Ramkumar, Bingnan Zhang, Carminia M Della Corte, Paul Robson, Stephen G Swisher, Jack A Roth, Bonnie S Glisson, David S Shames, Ignacio I Wistuba, Jing Wang, Vito Quaranta, John Minna, John V Heymach, Lauren Averett Byers
Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2...
January 5, 2021: Cancer Cell
Ahmed Salah, Yanqin Li, Hao Wang, Nianmin Qi, Yuehong Wu
Macrophages (Mϕs) play an essential role in maintaining body homeostasis. They perform dual functions produced by different subtypes. Mϕs not only fight against pathogens and foreign bodies such as bacteria or cancer cells but also participate in healing and repairing damaged tissue since they maintain both proinflammatory and anti-inflammatory effects sequentially. Tumors possess the ability to polarize Mϕs from proinflammatory M1 subtype to anti-inflammatory M2-like Mϕs called tumor-associated macrophages, which, in turn, help the tumors to acquire cancer hallmarks...
January 21, 2021: DNA and Cell Biology
Peng Lü, Songlin Qiu, Ye Pan, Feng Yu, Keping Chen
Digestive system cancers, including hepatocellular carcinoma, colorectal and gastric tumors, are characterized by high rates of incidence and mortality. Digestive cancers are difficult to diagnose during the early stages, and the side effects of chemotherapy are often severe and may outweigh the therapeutic benefits. Chimeric antibody chimeric antigen receptor T cell (CAR-T) therapy, a novel immunotherapy, has achieved excellent results for the treatment of hematological tumors. However, CAR-T treatment of solid tumors has struggled due to a lack of target specificity, a difficult tumor microenvironment, and T cell homing...
January 22, 2021: Cancer Biotherapy & Radiopharmaceuticals
Azadehsadat Razavi, Mahsa Keshavarz-Fathi, John Pawelek, Nima Rezaei
INTRODUCTION: In recent years, chimeric antigen receptor (CAR) T cell therapy has emerged for cancer treatment. After initial therapeutic success for hematologic malignancies, this approach has been extended for treatment of solid tumors including melanoma. AREAS COVERED: T cells need to be reprogramed to recognize specific antigens expressed only on tumor cells, a difficult problem since cancer cells are simply transformed normal cells. Tumor antigens, namely CSPG4, CD70, and GD2 have been targeted by CAR-T cells for melanoma...
January 22, 2021: Expert Review of Clinical Immunology
Anthony L Asher, Mohammed Ali Alvi, Mohamad Bydon, Nader Pouratian, Ronald E Warnick, James McInerney, Inga S Grills, Jason Sheehan
INTRODUCTION: Stereotactic radiosurgery (SRS) has been increasingly employed to treat patients with intracranial metastasis, both as a salvage treatment after failed whole brain radiation therapy (WBRT) and as an initial treatment. "Several studies have shown that SRS may be as effective as WBRT with the added benefit of preserving neuro-cognition". However, some patients may have local failure following SRS for intracranial metastasis, defined as increase in total lesion volume by 25% after at least 3 months of follow up...
January 22, 2021: Journal of Neuro-oncology
Mona M Ahmed, Manar G Gebriel, Emad A Morad, Ibrahim M Saber, Amira Elwan, Mona Salah, Ahmed E Fakhr, Amany M Shalaby, Mohamed A Alabiad
BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common cancer arising from the nasopharynx with a poor prognosis. Targeting immune checkpoint is one of the new promising lines in cancer treatment. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-ligand 1 (PD-L1) are immune checkpoints that regulate T-cell immune function. AIM: This work aimed to assess the immunohistochemical expression of PD-L1 and CTLA-4 in NPC and their ability to predict survival and response therapy and to check their validity as immunotherapy targets...
January 19, 2021: Applied Immunohistochemistry & Molecular Morphology: AIMM
Cheng Cui, Theresa Barberi, Rahul Suresh, Alan D Friedman
High-risk neuroblastomas harbor abundant myeloid cells that suppress anti-tumor immunity and support tumor growth. Macrophages lacking the inhibitory NF-κB p50 subunit adopt a pro-inflammatory phenotype. We now report that murine 9464D neuroblastoma cells, which express high levels of exogenous MYCN, grow slower in syngeneic p50(f/f);Lys-Cre mice that lack p50 in macrophages and neutrophils, compared with p50(f/f) littermates. Tumors in p50(f/f);Lys-Cre mice possess increased numbers of total and activated CD4+ and CD8+ T cells, and depletion of both of these T cell populations accelerates tumor growth...
January 22, 2021: Molecular Oncology
Tianyin Wang, Peiting Li, Tao Wan, Biao Tu, Jing Li, Feizhou Huang
Herein, a novel polymeric nanoparticle was designed to inhibit hepatoma carcinoma by simultaneously targeting the T cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor (PVR) and long noncoding RNAs antisense noncoding RNA in the INK4 locus (LncRNA ANRIL). Firstly, the siANRIL-loaded nanoparticles (NP-siANRIL) was developed by methoxy-poly (ethylene glycol)-polyamidoamine (mPEG-PAMAM) and polyamidoamine-poly (ethylene glycol)-disulfide bond-carboxyl (PAMAM-PEG-S2 -COOH) using the self-assembly method...
January 22, 2021: Journal of Drug Targeting
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