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(ox40 OR cd28 OR cd137 OR 4-1BB OR GITR OR ICOS OR CD27 OR CD40) AND (chimeric antigen receptor)

Carlos A Ramos, Rayne Rouce, Catherine S Robertson, Amy Reyna, Neeharika Narala, Gayatri Vyas, Birju Mehta, Huimin Zhang, Olga Dakhova, George Carrum, Rammurti T Kamble, Adrian P Gee, Zhuyong Mei, Meng-Fen Wu, Hao Liu, Bambi Grilley, Cliona M Rooney, Helen E Heslop, Malcolm K Brenner, Barbara Savoldo, Gianpietro Dotti
Second-generation (2G) chimeric antigen receptors (CARs) targeting CD19 are highly active against B cell malignancies, but it is unknown whether any of the costimulatory domains incorporated in the CAR have superior activity to others. Because CD28 and 4-1BB signaling activate different pathways, combining them in a single third-generation (3G) CAR may overcome the limitations of each individual costimulatory domain. We designed a clinical trial in which two autologous CD19-specific CAR-transduced T cell products (CD19...
September 13, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Sergey N Zolov, Skyler P Rietberg, Challice L Bonifant
Targeted adoptive immunotherapy with engineered T cells is a promising treatment for refractory hematologic malignancies. However, many patients achieving early complete remissions ultimately relapse. Immunosuppressive ligands are expressed on tumor and supportive cells in the tumor microenvironment (TME). When activated, T cells express associated "checkpoint" receptors. Binding of co-inhibitory ligands and receptors may directly contribute to T-cell functional exhaustion. It is not known whether all T cells engineered to express chimeric antigen receptors (CARs) are subject to checkpoint-mediated regulation...
October 8, 2018: Cytotherapy
Johannes Breuning, Brian Philip, Marion H Brown
T cells expressing chimeric antigen receptors (CARs) are a promising new cancer immunotherapy which has now reached the clinic. CARs are synthetic receptors that redirect T cells towards a tumour-associated antigen and activate them through various fused signalling regions, for example derived from CD3ζ, 4-1BB or CD28. Analysis of the optimal combination of CAR components including signalling domains is not yet comprehensive and may vary with the particular application. The C-terminus of the T cell surface receptor CD6 is critical for its costimulatory effects and signals through two phosphotyrosine motifs which bind to the intracellular adaptor proteins GADS and SLP-76...
October 9, 2018: Immunology
Hui Zhou, Yuling Luo, Sha Zhu, Xi Wang, Yunuo Zhao, Xuejin Ou, Tao Zhang, Xuelei Ma
BACKGROUND: Chimeric antigen receptor T (CAR T) cells immunotherapy is rapidly developed in treating cancers, especially relapsed or refractory B-cell malignancies. METHODS: To assess the efficacy and safety of CAR T therapy, we analyzed clinical trials from PUBMED and EMBASE. RESULTS: Results showed that the pooled response rate, 6-months and 1-year progression-free survival (PFS) rate were 67%, 65.62% and 44.18%, respectively. We observed that received lymphodepletion (72% vs 44%, P = 0...
September 26, 2018: BMC Cancer
Qi Zhong, Yang-Min Zhu, Li-Ling Zheng, Hui-Juan Shen, Rui-Ming Ou, Zhi Liu, Yan-Ling She, Rui Chen, Cheng Li, Jing Huang, Meng-Dong Yao, Qing Zhang, Shuang Liu
BACKGROUND: The second-generation CD19-chimeric antigen receptor (CAR)-T co-stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co-stimulatory domain appears to be longer. METHODS: The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package...
September 25, 2018: Acta Haematologica
Gongbo Li, Justin C Boucher, Hiroshi Kotani, Kyungho Park, Yongliang Zhang, Bishwas Shrestha, Xuefeng Wang, Lawrence Guan, Nolan Beatty, Daniel Abate-Daga, Marco L Davila
Chimeric antigen receptors (CARs) have an antigen-binding domain fused to transmembrane, costimulatory, and CD3ζ domains. Two CARs with regulatory approval include a CD28 or 4-1BB costimulatory domain. While both CARs achieve similar clinical outcomes, biologic differences have become apparent but not completely understood. Therefore, in this study we aimed to identify mechanistic differences between 4-1BB and CD28 costimulation that contribute to the biologic differences between the 2 CARs and could be exploited to enhance CAR T cell function...
September 20, 2018: JCI Insight
Jennifer A Rohrs, Dongqing Zheng, Nicholas A Graham, Pin Wang, Stacey D Finley
Chimeric antigen receptors (CARs) have recently been approved for the treatment of hematological malignancies, but our lack of understanding of the basic mechanisms that activate these proteins has made it difficult to optimize and control CAR-based therapies. In this study, we use phosphoproteomic mass spectrometry and mechanistic computational modeling to quantify the in vitro kinetics of individual tyrosine phosphorylation on a variety of CARs. We show that each of the 10 tyrosine sites on the CD28-CD3ζ CAR is phosphorylated by lymphocyte-specific protein-tyrosine kinase (LCK) with distinct kinetics...
August 22, 2018: Biophysical Journal
Elad Jacoby, Bella Bielorai, Abraham Avigdor, Orit Itzhaki, Daphna Hutt, Vered Nussboim, Amilia Meir, Adva Kubi, Michal Levy, Dragoslav Zikich, Li-At Zeltzer, Karin Brezinger, Jacob Schachter, Arnon Nagler, Michal J Besser, Amos Toren
Autologous CD19 chimeric-antigen receptor (CAR) T cells demonstrated remarkable remission rates in relapsed and refractory acute lymphoblastic leukemia (R/R ALL). Here, we report results from a phase 1b/2 study of in-house produced CD19 CAR with a CD28 costimulatory domain. Twenty-one patients with R/R ALL were enrolled, and 20 infused. The median age was 11 years (range, 5-48). Patients had a median of 4 prior regimens, including blinatumomab in 6 and prior stem-cell transplantation in 10. In total 8 patients had extramedullary (EM) leukemic involvement, and prior to lymphodepletion and CAR 7 had active lesions, a group underrepresented in previous trials...
September 6, 2018: American Journal of Hematology
Na An, Yun Nan Hou, Qiao Xia Zhang, Ting Li, Qiong Li Zhang, Cheng Fang, Huan Chen, Hon Cheung Lee, Yong Juan Zhao, Xin Du
Chimeric antigen receptor T cells (CAR-Ts) are a promising strategy for the treatment of many cancers, including multiple myeloma (MM), a hematological malignancy characterized by the high expression of CD38. To broaden the applications of using CD38 as a therapeutic target for the disease, we developed a new nanobody against CD38 and constructed a CD38-CAR that was composed of this nanobody as the targeting domain, and 4-1BB and CD3ζ as the costimulatory and activating domains, in a lentiviral vector. CD3+ T cells from healthy individuals were transduced with the CD38-CAR at an efficiency higher than 60%, as determined by CD38-CAR expression using flow cytometry...
October 1, 2018: Molecular Pharmaceutics
Alexander I Salter, Richard G Ivey, Jacob J Kennedy, Valentin Voillet, Anusha Rajan, Eva J Alderman, Uliana J Voytovich, Chenwei Lin, Daniel Sommermeyer, Lingfeng Liu, Jeffrey R Whiteaker, Raphael Gottardo, Amanda G Paulovich, Stanley R Riddell
Chimeric antigen receptors (CARs) link an antigen recognition domain to intracellular signaling domains to redirect T cell specificity and function. T cells expressing CARs with CD28/CD3ζ or 4-1BB/CD3ζ signaling domains are effective at treating refractory B cell malignancies but exhibit differences in effector function, clinical efficacy, and toxicity that are assumed to result from the activation of divergent signaling cascades. We analyzed stimulation-induced phosphorylation events in primary human CD8+ CD28/CD3ζ and 4-1BB/CD3ζ CAR T cells by mass spectrometry and found that both CAR constructs activated similar signaling intermediates...
August 21, 2018: Science Signaling
Erhao Zhang, Peiwei Yang, Jieyi Gu, Heming Wu, Xiaowei Chi, Chen Liu, Ying Wang, Jianpeng Xue, Weiyan Qi, Qingbo Sun, Shengnan Zhang, Jialiang Hu, Hanmei Xu
BACKGROUND: The therapeutic application of T cells endowing with chimeric antigen receptors (CARs) is faced with "on-target, off-tumor" toxicity against solid tumors, particularly in the treatment of the pancreatic cancer. To our best knowledge, the pancreatic cancer cell line AsPC-1 often highly expressed some distinct tumor-associated antigens, such as carcino-embryonic antigen (CEA) and mesothelin (MSLN). Therefore, in this research, we have characterized dual-receptor CAR-modified T cells (dCAR-T) that exert effective and safe cytotoxicity against AsPC-1 cells...
August 13, 2018: Journal of Hematology & Oncology
Anusha Thadi, Marian Khalili, William F Morano, Scott D Richard, Steven C Katz, Wilbur B Bowne
Peritoneal metastasis (PM) is an advanced stage malignancy largely refractory to modern therapy. Intraperitoneal (IP) immunotherapy offers a novel approach for the control of regional disease of the peritoneal cavity by breaking immune tolerance. These strategies include heightening T-cell response and vaccine induction of anti-cancer memory against tumor-associated antigens. Early investigations with chimeric antigen receptor T cells (CAR-T cells), vaccine-based therapies, dendritic cells (DCs) in combination with pro-inflammatory cytokines and natural killer cells (NKs), adoptive cell transfer, and immune checkpoint inhibitors represent significant advances in the treatment of PM...
August 10, 2018: Vaccines
Christopher W Helsen, Joanne A Hammill, Vivian W C Lau, Kenneth A Mwawasi, Arya Afsahi, Ksenia Bezverbnaya, Lisa Newhook, Danielle L Hayes, Craig Aarts, Bojana Bojovic, Galina F Denisova, Jacek M Kwiecien, Ian Brain, Heather Derocher, Katy Milne, Brad H Nelson, Jonathan L Bramson
Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors...
August 3, 2018: Nature Communications
Viktória Golumba-Nagy, Johannes Kuehle, Andreas A Hombach, Hinrich Abken
Adoptive cell therapy with chimeric antigen receptor (CAR)-redirected T cells induced spectacular regressions of leukemia and lymphoma, however, failed so far in the treatment of solid tumors. A cause is thought to be T cell repression through TGF-β, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-ζ CAR, but not with a 4-1BB-ζ CAR, resist TGF-β-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-β resistance; deleting the LCK-binding motif in the CD28 CAR abolished both IL-2 secretion and TGF-β resistance, while IL-2 add-back restored TGF-β resistance...
September 5, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Sophia Stock, Jean-Marc Hoffmann, Maria-Luisa Schubert, Lei Wang, Sanmei Wang, Wenjie Gong, Brigitte Neuber, Ulrike Gern, Anita Schmitt, Carsten Müller-Tidow, Peter Dreger, Michael Schmitt, Leopold Sellner
Enhanced in vivo expansion, long-term persistence of chimeric antigen receptor T (CART) cells, and efficient tumor eradication through these cells are linked to the proportion of less-differentiated cells in the CART cell product. Retronectin is well established as an adjuvant for improved retroviral transduction, while its property to enrich less-differentiated T cells is less known. In order to increase these subsets, this study investigated the effects of retronectin-mediated T-cell activation for CD19-specific CART cell production...
October 2018: Human Gene Therapy
Ai-Hong Zhang, Jeongheon Yoon, Yong Chan Kim, David W Scott
Controlling immune responses in autoimmunity and to biotherapeutics is an unmet need. In hemophilia, for example, up to one third of patients receiving therapeutic factor VIII (FVIII) infusions develop neutralizing Abs termed "inhibitors." To address this problem in a mouse model of hemophilia A, we used an Ag-specific regulatory T cell (Treg) approach in which we created a novel B cell-targeting chimeric receptor composed of an FVIII Ag domain linked with the CD28-CD3ζ transmembrane and signaling domains...
September 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Benjamin O Tschumi, Nina Dumauthioz, Bastien Marti, Lianjun Zhang, Pascal Schneider, Jean-Pierre Mach, Pedro Romero, Alena Donda
Adoptive transfer of T cells transduced with Chimeric Antigen Receptors (CAR) are now FDA-approved for the treatment of B-cell malignancies. Yet, the functionality of the endogenous TCR in CART cells has not been fully assessed. Here, we demonstrate that CART cells progressively upregulate Fas, FasL, DR5 and TRAIL, which result in their programmed cell death, independently of antigen-mediated TCR or CAR activation. CART cell apoptosis occurs even when the CAR contains a single (co-)activatory domain such as CD3ζ, CD28 or 4-1BB...
July 13, 2018: Journal for Immunotherapy of Cancer
Yali Han, Wei Xie, De-Gang Song, Daniel J Powell
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive disease that currently lacks effective targeted therapy. NKG2D ligands (NKG2DLs) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. METHODS: We applied a chimeric antigen receptor (CAR) approach for the targeting of NKG2DLs expressed on human TNBCs. Lentiviral vectors were used to express the extracellular domain of human NKG2D that binds various NKG2DLs, fused to signaling domains derived from T cell receptor CD3 zeta alone or with CD27 or 4-1BB (CD137) costimulatory domain...
July 6, 2018: Journal of Hematology & Oncology
Ayguen Sahin, Carlos Sanchez, Szofia Bullain, Peter Waterman, Ralph Weissleder, Bob S Carter
Glioblastoma multiforme (GBM) is the most aggressive and deadly form of adult brain cancer. Despite of many attempts to identify potential therapies for this disease, including promising cancer immunotherapy approaches, it remains incurable. To address the need of improved persistence, expansion, and optimal antitumor activity of T-cells in the glioma milieu, we have developed an EGFRvIII-specific third generation (G3-EGFRvIII) chimeric antigen receptor (CAR) that expresses both co-stimulatory factors CD28 and OX40 (MR1-CD8TM-CD28-OX40-CD3ζ)...
2018: PloS One
Hua-Ping Wei, Nan Yang, Zhen-Yang Gu, Sha-Sha Zhao, Fei-Yan Wang, Lan Luo, Li-Xun Guan, Chun-Ji Gao
OBJECTIVE: To explore the killing effect of CAR (CD138-CD28-CD3ζ)-NK cells on myeloma cells through construction of CAR(CD138-CD28-CD3)-NK cells. METHODS: The antiCD138scFv-CD28-CD3 zeta plasmid pcDNA3.1 was constructed, which then together with 3 plasmid lentiviral packaging system were transfected into 293T cells, the virus was collected. Furthermore, in order to get the stably transfected cell line, the NK92MI cell line was infected by the virus, then the positive cells were screened by puromycin...
June 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
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