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Engineered immune cells

Nasser K Yaghi, Jun Wei, Yuuri Hashimoto, Ling-Yuan Kong, Konrad Gabrusiewicz, Edjah K Nduom, Xiaoyang Ling, Neal Huang, Shouhao Zhou, Brittany C Parker Kerrigan, Jonathan M Levine, Virginia R Fajt, Gwendolyn Levine, Brian F Porter, Eric G Marcusson, Kiyoshi Tachikawa, Padmanabh Chivukula, David C Webb, Joseph E Payne, Amy B Heimberger
BACKGROUND: Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases. METHODS: We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects...
October 8, 2016: Neuro-oncology
J Wu, A Platero Luengo, M A Gil, K Suzuki, C Cuello, M Morales Valencia, I Parrilla, C A Martinez, A Nohalez, J Roca, E A Martinez, J C Izpisua Belmonte
More than eighteen years have passed since the first derivation of human embryonic stem cells (ESCs), but their clinical use is still met with several challenges, such as ethical concerns regarding the need of human embryos, tissue rejection after transplantation and tumour formation. The generation of human induced pluripotent stem cells (iPSCs) enables the access to patient-derived pluripotent stem cells (PSCs) and opens the door for personalized medicine as tissues/organs can potentially be generated from the same genetic background as the patient recipients, thus avoiding immune rejections or complication of immunosuppression strategies...
October 2016: Reproduction in Domestic Animals, Zuchthygiene
Walter H Moos, Carl A Pinkert, Michael H Irwin, Douglas V Faller, Krishna Kodukula, Ioannis P Glavas, Kosta Steliou
Preclinical Research Approximately 2,500 years ago, Hippocrates used the word herpes as a medical term to describe lesions that appeared to creep or crawl on the skin, advocating heat as a possible treatment. During the last 50 years, pharmaceutical research has made great strides, and therapeutic options have expanded to include small molecule antiviral agents, protease inhibitors, preventive vaccines for a handful of the papillomaviruses, and even cures for hepatitis C virus infections. However, effective treatments for persistent and recurrent viral infections, particularly the highly prevalent herpesviruses, continue to represent a significant unmet medical need, affecting the majority of the world's population...
October 20, 2016: Drug Development Research
Marco Ruella, Marcela V Maus
Immunotherapy is the revolution in cancer treatment of this last decade. Among multiple approaches able to harness the power of the immune system against cancer, T cell based immunotherapies represent one of the most successful examples. In particular, biotechnological engineering of protein structures, like the T cell receptor or the immunoglobulins, allowed the generation of synthetic peptides like chimeric antigen receptors and bispecific antibodies that are able to redirect non-tumor specific T cells to recognize and kill leukemic cells...
2016: Computational and Structural Biotechnology Journal
Zhengwei Wen, Qunying Jia, Xiaojuan Kang, Yongliang Lou, Lilin Zou, Jifeng Yang, Jimin Gao, Liping Han, Xiang Li
Interferon (IFN) regulates immune responses and antitumor activity. Arginine-glycine-aspartic acid (RGD) peptides can specifically bind to integrin αvβ3, a transmembrane receptor that is highly expressed on the surface of various cancer cells. In this study, we expressed recombinant RGD-IFN-α2a-core fusion proteins and assessed their antitumor activity in vitro. Two RGD-IFN-α2a-core fusion proteins and a negative control protein were expressed in vitro. These two RGD-IFN-α2a-core fusion proteins could bind the tumor cell surface specifically and did not bind to normal cells...
October 18, 2016: Anti-cancer Drugs
Kara W Moyes, Nicole Ap Lieberman, Shannon A Kreuser, Harrison Chinn, Conrad Winter, Gail Deutsch, Virginia Hoglund, Reid Watson, Courtney A Crane
In spite of their successes against hematologic malignancies, immunotherapeutic interventions for the treatment of patients with glioblastoma (GBM) have thus far been unsuccessful. This is in part due to the presence of a tumor microenvironment that fosters neoplastic growth and protects the tumor from destruction by the immune system. We have developed a novel genetically engineered macrophage-based platform with the potential to minimize the effects of the suppressive tumor microenvironment and improve innate and adaptive anti-tumor immune responses...
October 19, 2016: Human Gene Therapy
Balasubramanian Chandramouli, Caterina Bernacchioni, Danilo Di Maio, Paola Turano, Giuseppe Brancato
Ferritin molecular cages are marvelous 24-mer supramolecular architectures that enable massive iron storage (>2000 Fe atoms) within their inner cavity. This cavity is connected to the outer environment by two channels at C3 and C4 symmetry axes of the assembly. Ferritins can also be exploited as carriers for in vivo imaging and therapeutic applications, owing to their capability to effectively protect within the cage cavity synthetic non-endogenous agents and deliver them to targeted tissue cells without stimulating adverse immune responses...
October 18, 2016: Journal of Biological Chemistry
Bingjie Shi, Juan Li, Xuanling Shi, Wenxu Jia, Yi Wen, Xiongbing Hu, Fengfeng Zhuang, Jianzhong Xi, Linqi Zhang
Transcription activator-like effector nuclease (TALEN) represents a valuable tool for genomic engineering due to its single-nucleotide precision, high nuclease activity and low cytotoxicity. We report here systematic design and characterization of twenty eight novel TALENs targeting multiple regions of CCR5 gene (CCR5-TALEN) which encodes the co-receptor critical for entry of human immunodeficiency virus type I (HIV-1). By systemic characterization of these CCR5-TALENs, we have identified one (CCR5-TALEN-515) with higher nuclease activity, specificity and lower cytotoxicity compared to zinc-finger nuclease (CCR5-ZFN) currently undergoing clinical trials...
October 3, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Aaron F Cipriano, Amy Sallee, Myla Tayoba, Mayra C Cortez, Alan Lin, Ren-Guo Guan, Zhan-Yong Zhao, Huinan Liu
: Crystalline Mg-Zinc (Zn)-Strontium (Sr) ternary alloys consist of elements naturally present in the human body and provide attractive mechanical and biodegradable properties for a variety of biomedical applications. The first objective of this study was to investigate the degradation and cytocompatibility of four Mg-4Zn-xSr alloys (x = 0.15, 0.5, 1.0, 1.5 wt.%; designated as ZSr41A, B, C, and D respectively) in the direct culture with human umbilical vein endothelial cells (HUVEC) in vitro...
October 13, 2016: Acta Biomaterialia
Jianbin Wang, Michael C Holmes
The battle with human immunodeficiency virus (HIV) has been ongoing for more than 30 years, and although progress has been made, there are still significant challenges remaining. A few unique features render HIV to be one of the toughest viruses to conquer in the modern medicine era, such as the ability to target the host immune system, persist by integrating into the host genome and adapt to a hostile environment such as a single anti-HIV medication by continuously evolving. The finding of combination anti-retroviral therapy (cART) about 2 decades ago has transformed the treatment options for HIV-infected patients and significantly improved patient outcomes...
November 2016: Cytotherapy
(no author information available yet)
SynNotch T cells can promote antigen-specific delivery of cytokines or antibodies and direct cell fate.
October 14, 2016: Cancer Discovery
Januario E Castro, Thomas J Kipps
Treatment of patients with chronic lymphocytic leukemia and other B cell malignancies is evolving very rapidly. We have observed the quick transition during the last couple of years, from chemo-immunotherapy based treatments to oral targeted therapies based on B cell receptor signaling and Bcl-2 inhibitors, as well as the increasing use of second generation glyco-engineered antibodies. The next wave of revolution in the treatment for this conditions is approaching and it will be based on strategies that harness the power of the immune system to fight cancer...
March 2016: Best Practice & Research. Clinical Haematology
Guillermo S Romano Ibarra, Biswajit Paul, Blythe D Sather, Patrick M Younan, Karen Sommer, John P Kowalski, Malika Hale, Barry Stoddard, Jordan Jarjour, Alexander Astrakhan, Hans-Peter Kiem, David J Rawlings
A naturally occurring 32-base pair deletion of the HIV-1 co-receptor CCR5 has demonstrated protection against HIV infection of human CD4(+) T cells. Recent genetic engineering approaches using engineered nucleases to disrupt the gene and mimic this mutation show promise for HIV therapy. We developed a megaTAL nuclease targeting the third extracellular loop of CCR5 that we delivered to primary human T cells by mRNA transfection. The CCR5 megaTAL nuclease established resistance to HIV in cell lines and disrupted the expression of CCR5 on primary human CD4(+) T cells with a high efficiency, achieving up to 80% modification of the locus in primary cells as measured by molecular analysis...
August 23, 2016: Molecular Therapy. Nucleic Acids
Timothy Chao, Emma E Furth, Robert H Vonderheide
Tumor-associated neutrophils are increasingly recognized for their ability to promote tumor progression, mediate resistance to therapy, and regulate immunosuppression. Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Here, we report prominent expression of a neutrophil gene signature in a subset of human pancreatic adenocarcinoma (PDA). CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas...
October 13, 2016: Cancer Immunology Research
Shang-You Yang, Nora Strong, Xuan Gong, Michael H Heggeness
BACKGROUND: Stem cell-involved tissue engineering has gained dramatic attention as a therapeutic strategy for tissue regeneration including bone repair. However, the currently available possibilities to use embryonic stem cells and induced pluripotent stem cells (iPCs) face potential ethical issues, as well as risks of malignant transformation and immune rejection. Recently identified peripheral nerve-derived adult pluripotent cells (NEDAPS) that quickly proliferate after exposure to BMP-2 or nerve trauma and exhibit many embryonic stem cell characteristics may provide an attractive source cells for a variety of regenerative therapies...
October 10, 2016: Spine Journal: Official Journal of the North American Spine Society
Manishekhar Kumar, Jeannine M Coburn, David L Kaplan, Biman B Mandal
Macrophages, the key players in immunoregulation, are actively involved in tissue remodelling and vascularization. Recent advances in tissue engineering and regenerative medicine illustrate the importance of 'immuno-informed' biomaterials to regulate the microenvironment of biomedical implants. In the current study, silk-based 3D hydrogels were utilized to regulate cytokine delivery for macrophage, a type of immune cell, differentiation and polarization. Three different hydrogel variants, silk-poly(ethylene glycol) (PEG) (SP), silk-horseradish peroxidase (HRP) (SH) and silk-sonicated (SS) hydrogels were studied...
October 11, 2016: ACS Applied Materials & Interfaces
Bo-Ram Lee, Ho Kyung Ko, Ju Hee Ryu, Keum Young Ahn, Young-Ho Lee, Se Jin Oh, Jin Hee Na, Tae Woo Kim, Youngro Byun, Ick Chan Kwon, Kwangmeyung Kim, Jeewon Lee
Efficient delivery of tumor-specific antigens (TSAs) to lymph nodes (LNs) is essential to eliciting robust immune response for cancer immunotherapy but still remains unsolved. Herein, we evaluated the direct LN-targeting performance of four different protein nanoparticles with different size, shape, and origin [Escherichia coli DNA binding protein (DPS), Thermoplasma acidophilum proteasome (PTS), hepatitis B virus capsid (HBVC), and human ferritin heavy chain (hFTN)] in live mice, using an optical fluorescence imaging system...
October 11, 2016: Scientific Reports
Guido Ferrari, Barton F Haynes, Scott Koenig, Jeffrey L Nordstrom, David M Margolis, Georgia D Tomaras
HIV-1 is a retrovirus that integrates into host chromatin and can remain transcriptionally quiescent in a pool of immune cells. This characteristic enables HIV-1 to evade both host immune responses and antiretroviral drugs, leading to persistent infection. Upon reactivation of proviral gene expression, HIV-1 envelope (HIV-1 Env) glycoproteins are expressed on the cell surface, transforming latently infected cells into targets for HIV-1 Env-specific monoclonal antibodies (mAbs), which can engage immune effector cells to kill productively infected CD4(+) T cells and thus limit the spread of progeny virus...
October 7, 2016: Nature Reviews. Drug Discovery
Engin Baturcam, Natale Snape, Tiong Han Yeo, Johanna Schagen, Emma Thomas, Jayden Logan, Sally Galbraith, Natasha Collinson, Simon Phipps, Emmanuelle Fantino, Peter D Sly, Kirsten M Spann
Asthmatics are highly susceptible to respiratory viral infections, possibly due to impaired innate immunity. However, the exact mechanisms of susceptibility are likely to differ amongst viruses. Therefore, we infected primary nasal epithelial cells (NECs) from adults with mild-to-moderate asthma, with respiratory syncytial virus (RSV) or human metapneumovirus (hMPV) in vitro and investigated the antiviral response. NECs from these asthmatics supported elevated hMPV but not RSV infection, compared to non-asthmatic controls...
October 11, 2016: Journal of Innate Immunity
Masaki Morishita, Yuki Takahashi, Akihiro Matsumoto, Makiya Nishikawa, Yoshinobu Takakura
For cancer immunotherapy via tumor antigen vaccination in combination with an adjuvant, major challenges include the identification of a particular tumor antigen and efficient delivery of the antigen as well as adjuvant to antigen-presenting cells. In this study, we proposed an efficient exosome-based tumor antigens-adjuvant co-delivery system using genetically engineered tumor cell-derived exosomes containing endogenous tumor antigens and immunostimulatory CpG DNA. Murine melanoma B16BL6 cells were transfected with a plasmid vector encoding a fusion streptavidin (SAV; a protein that binds to biotin with high affinity)-lactadherin (LA; an exosome-tropic protein) protein, yielding genetically engineered SAV-LA-expressing exosomes (SAV-exo)...
December 2016: Biomaterials
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