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TCR Immunotherapy

Luciana D'Apice, Fausta Cuccaro, Sonia Varriale, Deborah Cipria, Rossella Sartorius, Paola Circosta, Alessandro Cignetti, Massimiliano Salerno, Maria R Coscia, Umberto Oreste, Vincenzo M Marzullo, Giuseppe Martini, Oreste Acuto, Piergiuseppe De Berardinis
Adoptive transfer of T lymphocytes (ACT) engineered with T-cell receptors (TCRs) of known antitumor specificity is an effective therapeutic strategy. However, a major constraint of ACT is the unpredictable interference of the endogenous TCR α and β chains in pairing of the transduced TCR. This effect reduces the efficacy of the genetically modified primary T cells and carries the risk of generating novel TCR reactivities with unintended functional consequences. Here, we show a powerful approach to overcome these limitations...
March 8, 2019: Journal of Immunotherapy
Connor J Dwyer, Hannah M Knochelmann, Aubrey S Smith, Megan M Wyatt, Guillermo O Rangel Rivera, Dimitrios C Arhontoulis, Eric Bartee, Zihai Li, Mark P Rubinstein, Chrystal M Paulos
Adoptive T cell transfer therapy (ACT) using tumor infiltrating lymphocytes or lymphocytes redirected with antigen receptors (CAR or TCR) has revolutionized the field of cancer immunotherapy. Although CAR T cell therapy mediates robust responses in patients with hematological malignancies, this approach has been less effective for treating patients with solid tumors. Additionally, toxicities post T cell infusion highlight the need for safer ACT protocols. Current protocols traditionally expand T lymphocytes isolated from patient tumors or from peripheral blood to large magnitudes in the presence of high dose IL-2 prior to infusion...
2019: Frontiers in Immunology
Benjamin E Willcox, Carrie R Willcox
In the version of this article initially published, the affiliations were incorrect. The correct affiliations are as follows: "1 Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. 2 Institute of Immunology and Immunotherapy, Cancer Immunology and Immunotherapy Centre, Cancer Research UK Birmingham Centre, University of Birmingham, Birmingham, UK." The reference citation at the end of the first sentence of the second paragraph of the subsection 'A perspective on current methods of ligand identification' was incorrect; the correct citation is "...
February 28, 2019: Nature Immunology
Robert J Mallis, Kristine N Brazin, Jonathan S Duke-Cohan, Wonmuk Hwang, Jia-Huai Wang, Gerhard Wagner, Haribabu Arthanari, Matthew J Lang, Ellis L Reinherz
Early studies of T cell structural biology using X-ray crystallography, surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) focused on a picture of the αβT cell receptor (αβTCR) component domains and their cognate ligands (peptides bound to MHC molecules, i.e. pMHCs) as static interaction partners. Moving forward requires integrating this corpus of data with dynamic technologies such as NMR, molecular dynamics (MD) simulations and real-time single molecule (SM) studies exemplified by optical tweezers (OT)...
February 27, 2019: Journal of Biomolecular NMR
Kota Iwahori, Yasushi Shintani, Soichiro Funaki, Yoko Yamamoto, Mitsunobu Matsumoto, Tetsuya Yoshida, Akiko Morimoto-Okazawa, Atsunari Kawashima, Eiichi Sato, Stephen Gottschalk, Meinoshin Okumura, Atsushi Kumanogoh, Hisashi Wada
Cancer immunotherapy, including immune checkpoint inhibitors, exerts beneficial effects in cancer patients. However, immune checkpoint inhibitors are only advantageous for a limited population of cancer patients. Therefore, companion diagnostics are needed in order to identify patients for whom these therapies are effective. In the present study, we evaluated detailed immunological aspects in clinical specimens from non-small cell lung cancer (NSCLC) patients. We analyzed the immune profiles, T cell cytotoxicity, and TCR repertoire of peripheral blood, normal lung tissue, and tumor tissue from NSCLC patients...
February 22, 2019: Scientific Reports
Manuel Effenberger, Andreas Stengl, Kilian Schober, Maria Gerget, Maximilian Kampick, Thomas R Müller, Dominik Schumacher, Jonas Helma, Heinrich Leonhardt, Dirk H Busch
Peptide-MHC (pMHC) multimers have become a valuable tool for immunological research, clinical immune monitoring, and immunotherapeutic applications. Biotinylated tetramers, reversible Streptamers, or dye-conjugated pMHC multimers are distinct pMHC reagents tailored for T cell identification, traceless T cell isolation, or TCR characterization, respectively. The specific applicability of each pMHC-based reagent is made possible either through conjugation of probes or reversible multimerization in separate production processes, which is laborious, time-consuming, and prone to variability between the different types of pMHC reagents...
February 13, 2019: Journal of Immunology: Official Journal of the American Association of Immunologists
Evgeni V Nikolaev, Andrew Zloza, Eduardo D Sontag
It was recently reported that acute influenza infection of the lung promoted distal melanoma growth in the dermis of mice. Melanoma-specific CD8+ T cells were shunted to the lung in the presence of the infection, where they expressed high levels of inflammation-induced cell-activation blocker PD-1, and became incapable of migrating back to the tumor site. At the same time, co-infection virus-specific CD8+ T cells remained functional while the infection was cleared. It was also unexpectedly found that PD-1 blockade immunotherapy reversed this effect...
2019: Frontiers in Immunology
Synat Kang, Yanyan Li, Yifeng Bao, Yi Li
Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1157-165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing...
February 5, 2019: Frontiers of Medicine
Ahdab Alsaieedi, Angelika Holler, Pedro Velica, Gavin Bendle, Hans J Stauss
We explored whether engineering of T cell specificity and effector function improves immunotherapy of solid tumors. Although IL-12 can enhance cancer immunity, a strategy of safe IL-12 delivery without toxicity is currently lacking. We engineered T cells to express IL-12 controlled by the NFAT promoter responsive to TCR stimulation, or by the Tet-On promoter responsive to doxycycline. In vivo , NFAT-engineered T cells caused lethal toxicity, while Tet-engineered T cells were safe in the absence of doxycycline...
2019: Oncoimmunology
Anthony Tanoto Tan, Ninghan Yang, Thinesh Lee Krishnamoorthy, Vincent Oei, Alicia Chua, Zhao Xinyuan, Tan Hui Si, Adeline Chia, Nina Le Bert, Diana Low, Hiang Keat Tan, Rajneesh Kumar, Farah Gillan Irani, Ho Zi Zong, Qi Zhang, Ernesto Guccione, Wai Lu-En, Sarene Koh, William Hwang, Wan Cheng Chow, Antonio Bertoletti
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is often associated with hepatitis B virus (HBV) infection. Cells of most HBV-related HCCs contain HBV DNA fragments that do not encode entire HBV antigens. We investigated whether these integrated HBV DNA fragments encode epitopes that are recognized by T cells and whether their presence in HCCs can be used to select HBV-specific T-cell receptors (TCRs) for immunotherapy. METHODS: HCC cells negative for HBV antigens, based on immunohistochemistry, were analyzed for the presence of HBV mRNAs by real-time PCR, sequencing, and Nanostring approaches...
January 31, 2019: Gastroenterology
Peng Wu, Tongtong Zhang, Baoyu Liu, Panyu Fei, Lei Cui, Rui Qin, Huaying Zhu, Danmei Yao, Ryan J Martinez, Wei Hu, Chenyi An, Yong Zhang, Junwei Liu, Jiawei Shi, Juan Fan, Weiwei Yin, Jie Sun, Chun Zhou, Xun Zeng, Chenqi Xu, Jianan Wang, Brian D Evavold, Cheng Zhu, Wei Chen, Jizhong Lou
TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation...
January 19, 2019: Molecular Cell
Guideng Li, Michael T Bethune, Stephanie Wong, Alok V Joglekar, Michael T Leonard, Jessica K Wang, Jocelyn T Kim, Donghui Cheng, Songming Peng, Jesse M Zaretsky, Yapeng Su, Yicheng Luo, James R Heath, Antoni Ribas, Owen N Witte, David Baltimore
T cell receptor (TCR) ligand discovery is essential for understanding and manipulating immune responses to tumors. We developed a cell-based selection platform for TCR ligand discovery that exploits a membrane transfer phenomenon called trogocytosis. We discovered that T cell membrane proteins are transferred specifically to target cells that present cognate peptide-major histocompatibility complex (MHC) molecules. Co-incubation of T cells expressing an orphan TCR with target cells collectively presenting a library of peptide-MHCs led to specific labeling of cognate target cells, enabling isolation of these target cells and sequencing of the cognate TCR ligand...
February 2019: Nature Methods
Ming Liu, Fukun Guo
Traditional cancer therapies include surgery, radiation, and chemotherapy, all of which are typically non-specific approaches. Cancer immunotherapy is a type of cancer treatment that helps the immune system fight cancer. Cancer immunotherapy represents a standing example of precision medicine: immune checkpoint inhibitors precisely target the checkpoints; tumor infiltrating lymphocytes, TCR T cells, and CAR T cells precisely kill cancer cells through tumor antigen recognition; and cancer vaccines are made from patient-derived dendritic cells, tumor cell DNA, or RNA, or oncolytic viruses, thus offering a type of personalized medicine...
September 2018: Precision Clinical Medicine
Nadia Mensali, Pierre Dillard, Michael Hebeisen, Susanne Lorenz, Theodossis Theodossiou, Marit Renée Myhre, Anne Fåne, Gustav Gaudernack, Gunnar Kvalheim, June Helen Myklebust, Else Marit Inderberg, Sébastien Wälchli
BACKGROUND: Adoptive T-cell transfer of therapeutic TCR holds great promise to specifically kill cancer cells, but relies on modifying the patient's own T cells ex vivo before injection. The manufacturing of T cells in a tailor-made setting is a long and expensive process which could be resolved by the use of universal cells. Currently, only the Natural Killer (NK) cell line NK-92 is FDA approved for universal use. In order to expand their recognition ability, they were equipped with Chimeric Antigen Receptors (CARs)...
January 18, 2019: EBioMedicine
Yang-Yang Liu, Qi-Fan Yang, Jing-Song Yang, Ru-Bo Cao, Jin-Yan Liang, Yu-Ting Liu, Yu-Lan Zeng, Si Chen, Xue-Feng Xia, Kai Zhang, Li Liu
Lung cancer is one of the greatest threats to human health, and is initially detected and attacked by the immune system through tumor-reactive T cells. The aim of this study was to determine the basic characteristics and clinical significance of the peripheral blood T-cell receptor (TCR) repertoire in patients with advanced lung cancer. To comprehensively profile the TCR repertoire, high-throughput sequencing was used to identify hypervariable rearrangements of complementarity determining region 3 (CDR3) of the TCR β chain in peripheral blood samples from 64 advanced lung cancer patients and 31 healthy controls...
January 21, 2019: International Journal of Cancer. Journal International du Cancer
Amélie Montel-Hagen, Christopher S Seet, Suwen Li, Brent Chick, Yuhua Zhu, Patrick Chang, Steven Tsai, Victoria Sun, Shawn Lopez, Ho-Chung Chen, Chongbin He, Chee Jia Chin, David Casero, Gay M Crooks
The ability to generate T cells from pluripotent stem cells (PSCs) has the potential to transform autologous T cell immunotherapy by facilitating universal, off-the-shelf cell products. However, differentiation of human PSCs into mature, conventional T cells has been challenging with existing methods. We report that a continuous 3D organoid system induced an orderly sequence of commitment and differentiation from PSC-derived embryonic mesoderm through hematopoietic specification and efficient terminal differentiation to naive CD3+ CD8αβ+ and CD3+ CD4+ conventional T cells with a diverse T cell receptor (TCR) repertoire...
January 4, 2019: Cell Stem Cell
Katie Hurst, Kiley A Lawrence, Matthew T Essman, Zeke J Walton, Lee R Leddy, Jessica E Thaxton
Tumor antigen-specific T cells rapidly lose energy and effector function in tumors. The cellular mechanisms by which energy loss and inhibition of effector function occur in tumor infiltrating lymphocytes (TILs) are ill-defined, and methods to identify tumor-antigen-specific TILs that experience such stress are unknown. Processes upstream of the mitochondria guide cell-intrinsic energy depletion. We hypothesized that a mechanism of T cell-intrinsic energy consumption was the process of oxidative protein folding and disulfide-bond formation that takes place in the endoplasmic reticulum (ER) guided by protein kinase R-like endoplasmic reticulum kinase (PERK) and downstream PERK axis target ER oxidoreductase 1 (ERO1α)...
January 18, 2019: Cancer Immunology Research
Rita Tendeiro Rego, Emma C Morris, Mark W Lowdell
Immunotherapy constitutes an exciting and rapidly evolving field, and the demonstration that genetically modified T-cell receptors (TCRs) can be used to produce T-lymphocyte populations of desired specificity offers new opportunities for antigen-specific T-cell therapy. Overall, TCR-modified T cells have the ability to target a wide variety of self and non-self targets through the normal biology of a T cell. Although major histocompatibility complex (MHC)-restricted and dependent on co-receptors, genetically engineered TCRs still present a number of characteristics that ensure they are an important alternative strategy to chimeric antigen receptors (CARs), and high-affinity TCRs can now be successfully engineered with the potential to enhance therapeutic efficacy while minimizing adverse events...
January 14, 2019: Cytotherapy
Vasyl Eisenberg, Shiran Hoogi, Astar Shamul, Tilda Barliya, Cyrille J Cohen
The last decade will be remembered as the dawn of the immunotherapy era during which we have witnessed the approval by regulatory agencies of genetically engineered CAR T-cells and of checkpoint inhibitors for cancer treatment. Understandably, T-lymphocytes represent the essential player in these approaches. These cells can mediate impressive tumor regression in terminally-ill cancer patients. Moreover, they are amenable to genetic engineering to improve their function and specificity. In the present review, we will give an overview of the most recent developments in the field of T-cell genetic engineering including TCR-gene transfer and CAR T-cells strategies...
January 14, 2019: Advanced Drug Delivery Reviews
Toshinobu Nishimura, Hiromitsu Nakauchi
Human induced pluripotent stem cells (iPSCs) are a potential source of blood cells for transfusion therapies and a promising tool for studying the ontogeny of hematopoiesis. The development of widely varying reprogramming methods has enabled us nowadays to obtain iPSCs even from a small number of antigen-specific T cells from patients. As these T-cell-derived iPSCs (T-iPSCs) carry TCR gene rearrangements in their genomic DNA, they are likely useful for producing antigen-specific T cells and for studying T-cell development...
2019: Methods in Molecular Biology
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