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TCR Immunotherapy

James T Neal, Xingnan Li, Junjie Zhu, Valeria Giangarra, Caitlin L Grzeskowiak, Jihang Ju, Iris H Liu, Shin-Heng Chiou, Ameen A Salahudeen, Amber R Smith, Brian C Deutsch, Lillian Liao, Allison J Zemek, Fan Zhao, Kasper Karlsson, Liora M Schultz, Thomas J Metzner, Lincoln D Nadauld, Yuen-Yi Tseng, Sahar Alkhairy, Coyin Oh, Paula Keskula, Daniel Mendoza-Villanueva, Francisco M De La Vega, Pamela L Kunz, Joseph C Liao, John T Leppert, John B Sunwoo, Chiara Sabatti, Jesse S Boehm, William C Hahn, Grace X Y Zheng, Mark M Davis, Calvin J Kuo
In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages)...
December 13, 2018: Cell
Valsamo Anagnostou, Patrick M Forde, James R White, Noushin Niknafs, Carolyn Hruban, Jarushka Naidoo, Kristen A Marrone, I K Ashok Sivakumar, Daniel C Bruhm, Samuel Rosner, Jillian Phallen, Alessandro Leal, Vilmos Adleff, Kellie N Smith, Tricia R Cottrell, Lamia Rhymee, Doreen N Palsgrove, Christine L Hann, Benjamin Levy, Josephine Feliciano, Christos Georgiades, Franco Verde, Peter Illei, Qing Kay Li, Edward Gabrielson, Malcolm V Brock, James M Isbell, Jennifer L Sauter, Janis Taube, Robert B Scharpf, Rachel Karchin, Drew M Pardoll, Jamie E Chaft, Matthew D Hellmann, Julie R Brahmer, Victor E Velculescu
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N=24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy whereas, non-responders had no significant changes or an increase in ctDNA levels...
December 12, 2018: Cancer Research
Boris I Chobrutskiy, Saif Zaman, Andrea Diviney, Moody M Mihyu, George Blanck
PURPOSE: In certain cancer settings, a T-cell response to cancer represents a relatively favorable outcome. Thus, the near-future challenges include a better understanding of exactly which T-cell features contribute to a response to which cancer antigen-groups, to maximize the opportunities for tumor-infiltrating lymphocyte (TIL)-based therapies and other immunotherapies. METHODS: The immune receptor complementarity determining region-3 (CDR3) is considered to be important for antigen binding, hence, in this report, we evaluated the chemical features of the CDR3 of 846 T-cell receptor-α (TCR-α) coding regions associated with bladder tumor tissue, using bioinformatics databases...
December 11, 2018: Journal of Cancer Research and Clinical Oncology
Ariel Isser, Jonathan P Schneck
Adoptive cell transfer (ACT) of engineered T cell receptors (TCRs) for cancer immunotherapy has evolved from simple gene transfer of isolated TCRs to various affinity enhancement techniques that overcome limitations imposed by central and peripheral tolerance on TCR affinity. In the current issue of the JCI, Poncette et al. used mice with human TCRαβ and HLA gene loci to discover CD4+ TCRs of optimal affinity for cancer testis antigen (CTA) NY-ESO-1. They combined this TCR with a previously discovered NY-ESO-1-specific CD8+ TCR in an ACT fibrosarcoma tumor model to demonstrate the importance of T cell help in mediating antitumor responses...
December 10, 2018: Journal of Clinical Investigation
Hakim Echchannaoui, Jutta Petschenka, Edite Antunes Ferreira, Beate Hauptrock, Carina Lotz-Jenne, Ralf-Holger Voss, Matthias Theobald
Genetic engineering of T cells with a T cell receptor (TCR) targeting tumor antigen is a promising strategy for cancer immunotherapy. Inefficient expression of the introduced TCR due to TCR mispairing may limit the efficacy and adversely affect the safety of TCR gene therapy. Here, we evaluated the safety and therapeutic efficiency of an optimized single-chain TCR (scTCR) specific for an HLA-A2.1-restricted (non-mutated) p53(264-272) peptide in adoptive T cell transfer (ACT) models using our unique transgenic mice expressing human p53 and HLA-A2...
November 15, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Bu-Nam Jeon, Hye-Ran Kim, Yun Shin Chung, Bo-Ra Na, Hyunkyung Park, Chorong Hong, Yasmin Fatima, Hyeonju Oh, Chang-Hyun Kim, Chang-Duk Jun
Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the OTI TCR CD8+ T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA-presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an 'inside-out' activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells...
2018: Oncoimmunology
Belinda Palermo, Ornella Franzese, Cosmo Di Donna, Mariangela Panetta, Concetta Quintarelli, Isabella Sperduti, Novella Gualtieri, Maria Laura Foddai, Enrico Proietti, Virginia Ferraresi, Gennaro Ciliberto, Paola Nisticò
We have recently described that DNA-damage inducing drug DTIC, administered before peptide (Melan-A and gp100)-vaccination, improves anti-tumor CD8+ Melan-A-specific T-cell functionality, enlarges the Melan-A+ TCR repertoire and impacts the overall survival of melanoma patients. To identify whether the two Ags employed in the vaccination differently shape the anti-tumor response, herein we have carried out a detailed analysis of phenotype, anti-tumor functionality and TCR repertoire in treatment-driven gp100-specific CD8+ T cells, in the same patients previously analyzed for Melan-A...
2018: Oncoimmunology
Jin-Huan Cui, Kai-Rong Lin, Song-Hua Yuan, Ya-Bin Jin, Xiang-Ping Chen, Xi-Kang Su, Jun Jiang, Ying-Ming Pan, Shao-Long Mao, Xiao-Fan Mao, Wei Luo
There is increasing evidence that deep sequencing-based T cell repertoire can sever as a biomarker of immune response in cancer patients; however, the characteristics of T cell repertoire including diversity and similarity, as well as its prognostic significance in patients with cervical cancer (CC) remain unknown. In this study, we applied a high throughput T cell receptor (TCR) sequencing method to characterize the T cell repertoires of peripheral blood samples from 25 CC patients, 30 cervical intraepithelial neoplasia (CIN) patients and 20 healthy women for understanding the immune alterations during the cervix carcinogenesis...
2018: Frontiers in Immunology
Guoliang Qiao, Xiao-Li Wang, Lei Zhou, Xin-Na Zhou, Yuguang Song, Shuo Wang, Lei Zhao, Michael A Morse, Amy Hobeika, Jin Song, Xin Yi, Xuefeng Xia, Jun Ren, Herbert Kim Lyerly
PURPOSE: We have assessed the combination of DC-CIK with S-1 plus cisplatin chemotherapy in advanced gastric cancer(AGC) and the role of mutational analysis of circulating tumor DNA(ctDNA) and T cell receptor (TCR) repertoire in predicting clinical outcomes. EXPERIMENTAL DESIGN: Consecutive patients (n=63) with advanced gastric cancer were allocated to treatment with S-1 alone, S-1 plus cisplatin, DC-CIK combined with S-1 or DC-CIK combined with S-1 plus cisplatin...
December 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Aaron M Miller, Milad Bahmanof, Dietmar Zehn, Ezra E W Cohen, Stephen P Schoenberger
Adoptive cellular therapy (ACT) using T-cell receptor (TCR)-engineered lymphocytes holds promise for eradication of disseminated tumors, but also an inherent risk of pathologic autoimmunity if targeted antigens or antigenic mimics are expressed by normal tissues. We evaluated whether modulating TCR affinity could allow CD8+ T cells to control tumor outgrowth without inducing concomitant autoimmunity in a preclinical murine model of ACT. RIP-mOVA mice express a membrane-bound form of chicken ovalbumin (mOVA) as a self-antigen in kidney and pancreas...
November 27, 2018: Cancer Immunology Research
Atsutaka Minagawa, Toshiaki Yoshikawa, Masaki Yasukawa, Akitsu Hotta, Mihoko Kunitomo, Shoichi Iriguchi, Maiko Takiguchi, Yoshiaki Kassai, Eri Imai, Yutaka Yasui, Yohei Kawai, Rong Zhang, Yasushi Uemura, Hiroyuki Miyoshi, Mahito Nakanishi, Akira Watanabe, Akira Hayashi, Kei Kawana, Tomoyuki Fujii, Tetsuya Nakatsura, Shin Kaneko
Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of "rejuvenated" induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8αβ T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) α chain gene during the CD4/CD8 double positive stage of in vitro differentiation...
November 1, 2018: Cell Stem Cell
Can Cui, Xiuyun Tian, Jianhui Wu, Chaoting Zhang, Qin Tan, Xiaoya Guan, Bin Dong, Min Zhao, Zheming Lu, Chunyi Hao
Pancreatic cancer is lethal due to lack of perceptible symptoms and effective treatment methods. Immunotherapy may provide promising therapeutic choices for malignant tumors like pancreatic cancer. Tumor infiltrating lymphocytes (TILs) in tumor mesenchyme could recognize peptide antigens presented on the surface of tumor cells. This study aimed to test the relationship between the TCR β repertoire of the tumor and peripheral blood, and also to investigate the intra-tumor spatial heterogeneity of the TCR β repertoire in pancreatic cancer...
November 13, 2018: Cancer Science
Sabrina A Hogan, Anaïs Courtier, Phil F Cheng, Nicoletta F Jaberg-Bentele, Simone M Goldinger, Manuarii Manuel, Solène Perez, Nadia Plantier, Jean-François Mouret, Thi Dan Linh Nguyen-Kim, Marieke Mi Raaijmakers, Pia Kvistborg, Nicolas Pasqual, John B A G Haanen, Reinhard Dummer, Mitchell P Levesque
Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4, however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment liquid biopsies from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA)...
November 13, 2018: Cancer Immunology Research
Dina Schneidman-Duhovny, Natalia Khuri, Guang Qiang Dong, Michael B Winter, Eric Shifrut, Nir Friedman, Charles S Craik, Kathleen P Pratt, Pedro Paz, Fred Aswad, Andrej Sali
Accurate predictions of T-cell epitopes would be useful for designing vaccines, immunotherapies for cancer and autoimmune diseases, and improved protein therapies. The humoral immune response involves uptake of antigens by antigen presenting cells (APCs), APC processing and presentation of peptides on MHC class II (pMHCII), and T-cell receptor (TCR) recognition of pMHCII complexes. Most in silico methods predict only peptide-MHCII binding, resulting in significant over-prediction of CD4 T-cell epitopes. We present a method, ITCell, for prediction of T-cell epitopes within an input protein antigen sequence for given MHCII and TCR sequences...
2018: PloS One
Aude I Segaliny, Guideng Li, Lingshun Kong, Ci Ren, Xiaoming Chen, Jessica K Wang, David Baltimore, Guikai Wu, Weian Zhao
Adoptive T cell transfer, in particular TCR T cell therapy, holds great promise for cancer immunotherapy with encouraging clinical results. However, finding the right TCR T cell clone is a tedious, time-consuming, and costly process. Thus, there is a critical need for single cell technologies to conduct fast and multiplexed functional analyses followed by recovery of the clone of interest. Here, we use droplet microfluidics for functional screening and real-time monitoring of single TCR T cell activation upon recognition of target tumor cells...
November 6, 2018: Lab on a Chip
Kazue Watanabe, Tomohide Tsukahara, Shingo Toji, Shogo Saitoh, Yoshihiko Hirohashi, Munehide Nakatsugawa, Terufumi Kubo, Takayuki Kanaseki, Hidekazu Kameshima, Takeshi Terui, Noriyuki Sato, Toshihiko Torigoe
For the efficacy of peptide vaccination immunotherapy for patients with cancer, endogenous expression of the target peptide/HLA on cancer cells is required. However, it is difficult to evaluate the expression status of a peptide/HLA complex because of the lack of a soluble T cell receptor (TCR) that reacts with TAA with high avidity. In this study, we developed two soluble TCR-multimers that were each directed to tumor-associated antigens (TAAs), survivin2B and PBF in the context of HLA-A24 (SVN-2B TCR-multimer and PBF TCR-multimer, respectively), from CTL clones that were established from peptide-vaccinated patients...
October 30, 2018: Cancer Science
Xuanhe Fu, Mingkai Xu, Yubo Song, Yongqiang Li, Huiwen Zhang, Jinghai Zhang, Chenggang Zhang
SEC2, a MHC II-dependent T cell mitogen, binds MHC II and TCR Vβs to induce effective co-stimulating signals for clonal T cell expansion. We previously characterized a SEC2 mutant with increased recognition to TCR Vβs, ST-4, which could intensify NF-κB signaling transduction, leading to IL-2 production and T cell activation. In this study, we found that in contrast to SEC2, ST-4 could induce murine CD4+ T cell proliferation in a Vβ8.2- and Vβ8.3-specific manner in the absence of MHC II+ APCs. Furthermore, although IL-2 secretion in response to either SEC2 or ST-4 stimulation was accompanied by upregulation of PKCθ, IKKα/β, IκBα, and NF-κB in mouse splenocytes, only ST-4 could activate CD4+ T cells in the absence of MHC II+ APCs through the PKCθ/NF-κB signaling pathway...
October 23, 2018: Journal of Biological Chemistry
Soyoko Morimoto, Fumihiro Fujiki, Kenta Kondo, Hiroko Nakajima, Yoshiki Kobayashi, Miki Inatome, Nao Aoyama, Yuya Nishida, Akihiro Tsuboi, Yoshihiro Oka, Sumiyuki Nishida, Jun Nakata, Naoki Hosen, Yusuke Oji, Haruo Sugiyama
Adoptive T-cell therapy with T cell receptor (TCR) -engineered T cells is an attractive strategy for cancer treatment and the success in this therapy is dependent on the functional avidity of the transduced TCRs against targeted tumor antigens. Therefore, the establishment of the methodology of the efficient and precise evaluation of TCR functional avidity has been awaited. Here, we show a novel platform cell line, named 2D3, which enables the functional avidity of transduced TCRs to be evaluated efficiently and precisely...
September 25, 2018: Oncotarget
Maria Soler, Xiaokang Li, Aurelian John-Herpin, Julien Schmidt, George Coukos, Hatice Altug
The screening and analysis of T cells functional avidity for specific tumor-associated antigens is crucial for the development of personalized immunotherapies against cancer. The affinity and kinetics of a T cell receptor (TCR) binding to the peptide-major histocompatibility complex (pMHC), expressed on tumor or antigen-presenting cells, have shown major implications in T cell activation and effector functions. We introduce an innovative methodology for the two-dimensional affinity analysis of TCR-pMHC in a label-free configuration by employing a multiparametric Surface Plasmon Resonance biosensor (MP-SPR) functionalized with artificial cell membranes...
October 19, 2018: ACS Sensors
Soyoung A Oh, Akiko Seki, Sascha Rutz
CRISPR/Cas9 has enabled the rapid and efficient generation of gene knockouts across various cell types of several species. T cells are central players in adaptive immune responses. Gene editing in primary T cells not only represents a valuable research tool, but is also critical for next generation immunotherapies, such as CAR T cells. Broad application of CRIPSR/Cas9 for gene editing in primary T cells has been hampered by limitations in transfection efficiency and the requirement for TCR stimulation. In this article, we provide a detailed protocol for Cas9/gRNA ribonucleoprotein (RNP) transfection of primary mouse and human T cells without the need for TCR stimulation that achieves near complete loss of target gene expression at the population level...
October 18, 2018: Current Protocols in Immunology
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