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TCR Immunotherapy

Rami Yossef, Eric Tran, Drew C Deniger, Alena Gros, Anna Pasetto, Maria R Parkhurst, Jared J Gartner, Todd D Prickett, Gal Cafri, Paul F Robbins, Steven A Rosenberg
Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TILs) targeting neoantigens can mediate tumor regression in selected patients with metastatic epithelial cancer. However, effectively identifying and harnessing neoantigen-reactive T cells for patient treatment remains a challenge and it is unknown whether current methods to detect neoantigen-reactive T cells are missing potentially clinically relevant neoantigen reactivities. We thus investigated whether the detection of neoantigen-reactive TILs could be enhanced by enriching T cells that express PD-1 and/or T cell activation markers followed by microwell culturing to avoid overgrowth of nonreactive T cells...
October 4, 2018: JCI Insight
Emmanuelle Benard, Jacques A Nunès, Laurent Limozin, Kheya Sengupta
We created APC-mimetic synthetic substrates to study the impact of ligand clustering on T cell activation and spreading. The substrates exhibit antibodies directed against the TCR-complex in the form of a patterned array of sub micrometric dots surrounded by a fluid supported lipid bilayer (SLB) which may itself be functionalized with another bio-molecule. We show that for T cell adhesion mediated by T cell receptor (TCR) alone, in the patterned, but not in the corresponding homogeneous controls, the TCR, ZAP-70 and actin are present in the form of clusters or patches that co-localize with the ligand-dots...
2018: Frontiers in Immunology
Mohamed L Salem, Sabry A El-Naggar, Heba A Mahmoud, Rehab M Elgharabawy, Abeer M Bader
Although the majority of cancers respond to chemotherapy, most cancer types relapse, at least in part, due to the poor immunogenicity of most tumor. We have reported before that treatment of tumor bearing mice with a combination of the anti-cancer chemotherapy cyclophosphamide (CTX) and immunotherapy can result in complete tumor regression using T-cell receptor (TCR) transgenic CD8+ T cells specific to antigens. This study aimed to determine whether chemotherapy can cure immunogenic tumor which expresses non-self-tumor antigen and result in antitumor immunity...
January 2018: International Journal of Immunopathology and Pharmacology
Pauline L de Goeje, Yarne Klaver, Margaretha E H Kaijen-Lambers, Anton W Langerak, Heleen Vroman, André Kunert, Cor H J Lamers, Joachim G J V Aerts, Reno Debets, Rudi W Hendriks
Introduction: Malignant pleural mesothelioma (MPM) is a malignancy with a very poor prognosis for which new treatment options are urgently needed. We have previously shown that dendritic cell (DC) immunotherapy provides a clinically feasible treatment option. In the current study, we set out to assess the immunological changes induced by DC immunotherapy in peripheral blood of MPM patients. Methods: Peripheral blood was collected from nine patients enrolled in a phase I dose escalation study, before and after treatment with DCs that were pulsed with an allogeneic tumor lysate preparation consisting of a mixture of five cultured mesothelioma cell lines...
2018: Frontiers in Immunology
Mariko Takami, Fumie Ihara, Shinichiro Motohashi
Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to T-cell receptor (TCR) stimulation by recognizing antigens such as α-galactosylceramide (α-GalCer) presented on CD1d; thus, orchestrating other immune cells to fight against pathogen infection and tumors. Because of their ability to induce strong anti-tumor responses and the convenience of their invariant TCR activated by a synthetic ligand, α-GalCer, iNKT cells have been intensively studied for application in immunotherapeutic approaches to treat cancer patients in the clinic...
2018: Frontiers in Immunology
Andreas Wieland, Alice O Kamphorst, N Volkan Adsay, Jonathan J Masor, Juan Sarmiento, Tahseen H Nasti, Sam Darko, Daniel C Douek, Yue Xue, Walter J Curran, David H Lawson, Rafi Ahmed
PD-1-targeted therapy has dramatically changed advanced cancer treatment. However, many questions remain, including specificity of T cells activated by PD-1 therapy and how peripheral blood analysis correlates to effects at tumor sites. In this study, we utilized TCR sequencing to dissect the composition of peripheral blood CD8 T cells activated upon therapy, comparing it with tumor-infiltrating lymphocytes. We report on a nonagenarian melanoma patient who showed a prominent increase in peripheral blood Ki-67 + CD8 T cells following brain stereotactic radiation and anti-PD-1 immunotherapy...
August 22, 2018: Cancer Immunology, Immunotherapy: CII
Stéphanie Corgnac, Marie Boutet, Maria Kfoury, Charles Naltet, Fathia Mami-Chouaib
Cancer immunotherapy is aimed at stimulating tumor-specific cytotoxic T lymphocytes and their subsequent trafficking so that they may reach, and persist in, the tumor microenvironment, recognizing and eliminating malignant target cells. Thus, characterization of the phenotype and effector functions of CD8+ T lymphocytes infiltrating human solid tumors is essential for better understanding and manipulating the local antitumor immune response, and for defining their contribution to the success of current cancer immunotherapy approaches...
2018: Frontiers in Immunology
Zhuting Hu, Annabelle J Anandappa, Jing Sun, Jintaek Kim, Donna E Leet, David J Bozym, Christina Chen, Louise Williams, Sachet A Shukla, Wandi Zhang, Diana Tabbaa, Scott Steelman, Oriol Olive, Kenneth J Livak, Hiroyuki Kishi, Atsushi Muraguchi, Indira Guleria, Jonathan Stevens, William J Lane, Ute E Burkhardt, Edward F Fritsch, Donna Neuberg, Patrick A Ott, Derin B Keskin, Nir Hacohen, Catherine J Wu
Recent studies have highlighted the promise of targeting tumor neoantigens to generate potent anti-tumor immune responses, and provides strong motivation for improving our understanding of antigen-T cell receptor (TCR) interactions. Advances in single-cell sequencing technologies have opened the door for detailed investigation of the TCR repertoire, providing paired information from TCRα and TCRβ, which together determine specificity. However, a need remains for efficient methods to assess the specificity of discovered TCRs...
August 27, 2018: Blood
Kalyani Pyaram, Viveka Nand Yadav
Type I or invariant natural killer T cells belong to a unique lineage of innate T cells, which express markers of both T lymphocytes and NK cells, namely T cell receptor (TCR) and NK1.1 (CD161C), respectively. Thus, apart from direct killing of target cells like NK cells, and they also produce a myriad of cytokines which modulate the adaptive immune responses. Unlike traditional T cells which carry a conventional αβ TCR, NKT cells express semi-invariant TCR - Vα14-Jα18, coupled with Vβ8, Vβ7 and Vβ2 in mice...
2018: Journal of Cancer Science & Therapy
Patricia Mercier-Letondal, Chrystel Marton, Marina Deschamps, Christophe Ferrand, Charline Vauchy, Clément Chenut, Aurélie Baguet, Olivier Adotévi, Christophe Borg, Jeanne Galaine, Yann Godet
High-risk human papillomavirus (HPV) infection is a causal factor in oropharyngeal and gynecological malignancies, and development of HPV-targeted immunotherapy could be used to treat patients with these cancers. T cell-mediated adoptive immunotherapy targeting E6 and E7, two HPV16 proteins consistently expressed in tumor cells, appears to be both attractive and safe. However, isolation of HPV-specific T cells is difficult owing to the low frequency of these cell precursors in the peripheral blood. In addition, HPV-positive cancer cells often down-regulate major histocompatibility complex (MHC) class I expression ex vivo, limiting the efficacy of MHC class I-restricted approaches...
October 2018: Human Gene Therapy
Michelle Miron, Brahma V Kumar, Wenzhao Meng, Tomer Granot, Dustin J Carpenter, Takashi Senda, Dora Chen, Aaron M Rosenfeld, Bochao Zhang, Harvey Lerner, Amy L Friedman, Uri Hershberg, Yufeng Shen, Adeeb Rahman, Eline T Luning Prak, Donna L Farber
Translating studies on T cell function and modulation from mouse models to humans requires extrapolating in vivo results on mouse T cell responses in lymphoid organs (spleen and lymph nodes [LN]) to human peripheral blood T cells. However, our understanding of T cell responses in human lymphoid sites and their relation to peripheral blood remains sparse. In this study, we used a unique human tissue resource to study human T cells in different anatomical compartments within individual donors and identify a subset of memory CD8+ T cells in LN, which maintain a distinct differentiation and functional profile compared with memory CD8+ T cells in blood, spleen, bone marrow, and lungs...
October 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Asen Bagashev, Elena Sotillo, Chih-Hang Anthony Tang, Kathryn L Black, Jessica Perazzelli, Steven H Seeholzer, Yair Argon, David M Barrett, Stephan A Grupp, Chih-Chi Andrew Hu, Andrei Thomas-Tikhonenko
We have previously described a mechanism of acquired resistance of B-cell acute lymphoblastic leukemia to CD19-directed chimeric antigen receptor T-cell (CART) immunotherapy. It was based on in-frame insertions in or skipping of CD19 exon 2. To distinguish between epitope loss and defects in surface localization, we used retroviral transduction and genome editing to generate cell lines expressing CD19 exon 2 variants (CD19ex2vs) bearing VSV-G tags. These lines were negative by live-cell flow cytometry with an anti-VSV-G antibody and resistant to killing by VSV-G directed antibody-drug conjugates (ADC), suggestive of a defect in surface localization...
August 13, 2018: Molecular and Cellular Biology
Bianca Simon, Manuel Wiesinger, Johannes März, Kilian Wistuba-Hamprecht, Benjamin Weide, Beatrice Schuler-Thurner, Gerold Schuler, Jan Dörrie, Ugur Uslu
Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR...
August 11, 2018: International Journal of Molecular Sciences
David Bending, Masahiro Ono
Studies on regulatory T cells (Treg) have focused on thymic Treg as a stable lineage of immunosuppressive T cells, the differentiation of which is controlled by the transcription factor Foxp3. This lineage perspective, however, may constrain hypotheses regarding the role of Foxp3 and Treg in vivo, particularly in clinical settings and immunotherapy development. In this review, we synthesise a new perspective on the role of Foxp3 as a dynamically expressed gene, and thereby revisit the molecular mechanisms for the transcriptional regulation of Foxp3...
August 4, 2018: Clinical and Experimental Immunology
Aras Toker, Linh T Nguyen, Simone C Stone, S Y Cindy Yang, Sarah Rachel Katz, Patricia A Shaw, Blaise A Clarke, Danny Ghazarian, Ayman Al-Habeeb, Alexandra Easson, Wey L Leong, David R McCready, Michael Reedijk, Cynthia J Guidos, Trevor J Pugh, Marcus Q Bernardini, Pamela S Ohashi
Purpose: Regulatory T (Treg) cells expressing the transcription factor FOXP3 are essential for the maintenance of immunologic self-tolerance but play a detrimental role in most cancers due to their ability to suppress antitumor immunity. The phenotype of human circulating Treg cells has been extensively studied, but less is known about tumor-infiltrating Treg cells. We studied the phenotype and function of tumor-infiltrating Treg cells in ovarian cancer and melanoma to identify potential Treg cell-associated molecules that can be targeted by tumor immunotherapies...
July 31, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yinnian Feng, Ellis L Reinherz, Matthew J Lang
T lymphocytes use αβ T cell receptors (TCRs) to recognize sparse antigenic peptides bound to MHC molecules (pMHCs) arrayed on antigen-presenting cells (APCs). Contrary to conventional receptor-ligand associations exemplified by antigen-antibody interactions, forces play a crucial role in nonequilibrium mechanosensor-based T cell activation. Both T cell motility and local cytoskeleton machinery exert forces (i.e., generate loads) on TCR-pMHC bonds. We review biological features of the load-dependent activation process as revealed by optical tweezers single molecule/single cell and other biophysical measurements...
August 2018: Trends in Immunology
Leah V Sibener, Ricardo A Fernandes, Elizabeth M Kolawole, Catherine B Carbone, Fan Liu, Darren McAffee, Michael E Birnbaum, Xinbo Yang, Laura F Su, Wong Yu, Shen Dong, Marvin H Gee, Kevin M Jude, Mark M Davis, Jay T Groves, William A Goddard, James R Heath, Brian D Evavold, Ronald D Vale, K Christopher Garcia
TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR...
July 26, 2018: Cell
Giulia Escobar, Luigi Barbarossa, Giulia Barbiera, Margherita Norelli, Marco Genua, Anna Ranghetti, Tiziana Plati, Barbara Camisa, Chiara Brombin, Davide Cittaro, Andrea Annoni, Attilio Bondanza, Renato Ostuni, Bernhard Gentner, Luigi Naldini
Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses...
July 24, 2018: Nature Communications
Haralambos Tzoupis, Theodore Tselios
Advances in theoretical chemistry have led to the development of various robust computational techniques employed in drug design. Pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulations have been extensively applied, separately or in combination, in the design of potent molecules. The techniques involve the identification of a potential drug target (e.g., protein) and its subsequent characterization. The next step in the process comprises the development of a map describing the interaction patterns between the target molecule and its natural substrate...
2018: Methods in Molecular Biology
Claudia Juraske, Piyamaporn Wipa, Anna Morath, Jose Villacorta Hidalgo, Frederike A Hartl, Katrin Raute, Hans-Heinrich Oberg, Daniela Wesch, Paul Fisch, Susana Minguet, Sutatip Pongcharoen, Wolfgang W Schamel
T lymphocytes expressing the γδ T cell receptor (γδ TCR) can recognize antigens expressed by tumor cells and subsequently kill these cells. γδ T cells are indeed used in cancer immunotherapy clinical trials. The anti-CD3ε antibody UCHT1 enhanced the in vitro tumor killing activity of human γδ T cells by an unknown molecular mechanism. Here, we demonstrate that Fab fragments of UCHT1, which only bind monovalently to the γδ TCR, also enhanced tumor killing by expanded human Vγ9Vδ2 γδ T cells or pan-γδ T cells of the peripheral blood...
2018: Frontiers in Immunology
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