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

Hongwei Du, Koichi Hirabayashi, Sarah Ahn, Nancy Porterfield Kren, Stephanie Ann Montgomery, Xinhui Wang, Karthik Tiruthani, Bhalchandra Mirlekar, Daniel Michaud, Kevin Greene, Silvia Gabriela Herrera, Yang Xu, Chuang Sun, Yuhui Chen, Xingcong Ma, Cristina Rosa Ferrone, Yuliya Pylayeva-Gupta, Jen Jen Yeh, Rihe Liu, Barbara Savoldo, Soldano Ferrone, Gianpietro Dotti
The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3...
February 11, 2019: Cancer Cell
MyLinh T Duong, Matthew R Collinson-Pautz, Eva Morschl, An Lu, Slawomir P Szymanski, Ming Zhang, Mary E Brandt, Wei-Chun Chang, Kelly L Sharp, Steven M Toler, Kevin M Slawin, Aaron E Foster, David M Spencer, J Henri Bayle
Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow in vivo elimination of CAR-T cells...
March 29, 2019: Molecular Therapy Oncolytics
Sophia Stock, Rudolf Übelhart, Maria-Luisa Schubert, Fuli Fan, Bailin He, Jean-Marc Hoffmann, Lei Wang, Sanmei Wang, Wenjie Gong, Brigitte Neuber, Angela Hückelhoven-Krauss, Ulrike Gern, Christiane Christ, Monika Hexel, Anita Schmitt, Patrick Schmidt, Jürgen Krauss, Dirk Jäger, Carsten Müller-Tidow, Peter Dreger, Michael Schmitt, Leopold Sellner
Despite encouraging results with chimeric antigen receptor T (CART) cells, outcome can still be improved by optimization of the CART cell generation process. The proportion of less-differentiated T cells within the transfused product is linked to enhanced in vivo CART cell expansion and long-term persistence. The clinically approved PI3Kδ inhibitor idelalisib is well established in the treatment of B cell malignancies. Besides B cell receptor pathway inhibition, idelalisib can modulate T cell differentiation and function...
February 9, 2019: International Journal of Cancer. Journal International du Cancer
Fatemeh Hajari Taheri, Mahmoud Hassani, Zahra Sharifzadeh, Mehdi Behdani, Arash Arashkia, Mohsen Abolhassani
Solid tumors that are responsible for more than 85% of cancer death cases need angiogenesis for their growth and metastasis. Among antiangiogenic therapies, targeting the vascular endothelial growth factor receptor 2 (VEGFR2) that is over-expressed on tumor vasculatures has been a promising strategy. In this study, we developed a second generation nanobody (VHH)-based CAR T cell targeting VEGFR2-expressing tumor cells. The CAR T cell was developed by linking the anti-VEGFR2 VHH to a spacer, and signaling domains of CD28 and CD3 ζ...
February 6, 2019: IUBMB Life
Rüdiger Klapdor, Shuo Wang, Michael Morgan, Thilo Dörk, Ulrich Hacker, Peter Hillemanns, Hildegard Büning, Axel Schambach
Novel therapeutic approaches against ovarian cancer (OC) are urgently needed because of its high rate of recurrence even after extensive surgery and multi-agent chemotherapy. We aimed to develop a novel anti-CD24 chimeric antigen receptor (CAR) as an immunotherapeutic approach against OC cells and cancer stem cells (CSC). CSC represents a subpopulation of the tumor characterized by enhanced chemoresistance as well as the increased capability of self-renewal and metastasis. We designed a codon-optimized third-generation CAR containing the highly active single chain variable fragment (scFv) "SWA11" against CD24...
February 3, 2019: International Journal of Molecular Sciences
Lin Ye, Yuqing Lou, Liming Lu, Xiaohong Fan
Non-small cell lung cancer (NSCLC) and mesothelioma are renowned for being diagnosed at a late stage and poor prognosis. Although surgery, chemotherapy, and radiotherapy have yielded successful outcomes, the improvement on the survival rate of NSCLC and mesothelioma have been less marked. Recently, adoptive immunotherapy, particularly chimeric antigen receptor T (CAR-T) cell therapy demonstrated promise for improving the survival of acute lymphoblastic leukemia with minimum toxicity. However, its application in solid tumors still warrants in-depth investigations and multiple consistent trial results, particularly in eliminating 'off-tumor' toxicity...
January 2019: Experimental and Therapeutic Medicine
Rodolfo Garza-Morales, Jose J Perez-Trujillo, Elvis Martinez-Jaramillo, Odila Saucedo-Cardenas, Maria J Loera-Arias, Aracely Garcia-Garcia, Humberto Rodriguez-Rocha, Esma Yolcu, Haval Shirwan, Jorge G Gomez-Gutierrez, Roberto Montes-de-Oca-Luna
The SA-4-1BBL, an oligomeric novel form of the natural ligand for the 4-1BB co-stimulatory receptor of the tumor necrosis factor (TNF) superfamily, as a recombinant protein has potent pleiotropic effects on cells of innate, adaptive, and regulatory immunity with demonstrated therapeutic efficacy in several tumor models. However, the production of soluble form of SA-4-1BBL protein and quality control is time and resource intensive and face various issues pertinent to clinical development of biologics. The present study sought to take advantage of the simplicity and translatability of DNA-based vaccines for the production and delivery of SA-4-1BBL for cancer immune prevention and therapy...
January 15, 2019: Cancers
Maria Castella, Anna Boronat, Raquel Martín-Ibáñez, Vanina Rodríguez, Guillermo Suñé, Miguel Caballero, Berta Marzal, Lorena Pérez-Amill, Beatriz Martín-Antonio, Julio Castaño, Clara Bueno, Olga Balagué, Europa Azucena González-Navarro, Carles Serra-Pages, Pablo Engel, Ramon Vilella, Daniel Benitez-Ribas, Valentín Ortiz-Maldonado, Joan Cid, Jaime Tabera, Josep M Canals, Miquel Lozano, Tycho Baumann, Anna Vilarrodona, Esteve Trias, Elías Campo, Pablo Menendez, Álvaro Urbano-Ispizua, Jordi Yagüe, Patricia Pérez-Galán, Susana Rives, Julio Delgado, Manel Juan
Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells in vitro , inducing secretion of pro-inflammatory cytokines and CAR T cell proliferation...
March 15, 2019: Molecular Therapy. Methods & Clinical Development
Christopher Ronald Funk, Christopher T Petersen, Neera Jagirdar, Sruthi Ravindranathan, David L Jaye, Christopher R Flowers, Amelia Langston, Edmund K Waller
Clinical trials of chimeric antigen receptor (CAR) T cells in hematologic malignancy associate remissions with two profiles of CAR T cell proliferation kinetics, which differ based upon costimulatory domain. Additional T cell intrinsic factors that influence or predict clinical response remain unclear. To address this gap, we report the case of a 68-year-old woman with refractory/relapsed diffuse large B cell lymphoma (DLBCL), treated with tisagenlecleucel (anti-CD19), with a CD137 costimulatory domain (4-1BB) on an investigational new drug application (#16944)...
December 19, 2018: International Journal of Molecular Sciences
Judith Feucht, Jie Sun, Justin Eyquem, Yu-Jui Ho, Zeguo Zhao, Josef Leibold, Anton Dobrin, Annalisa Cabriolu, Mohamad Hamieh, Michel Sadelain
Chimeric antigen receptors (CARs) are synthetic receptors that target and reprogram T cells to acquire augmented antitumor properties1 . CD19-specific CARs that comprise CD28 and CD3ζ signaling motifs2 have induced remarkable responses in patients with refractory leukemia3-5 and lymphoma6 and were recently approved by the US Food and Drug Administration7 . These CARs program highly performing effector functions that mediate potent tumor elimination4,8 despite the limited persistence they confer on T cells3-6,8 ...
December 17, 2018: Nature Medicine
Dina Schneider, Ying Xiong, Peirong Hu, Darong Wu, Weizao Chen, Tianlei Ying, Zhongyu Zhu, Dimiter S Dimitrov, Boro Dropulic, Rimas J Orentas
Acute myeloid leukemia (AML) remains a challenging pediatric and adult disease. Given the elevated expression of the CD33 antigen on leukemic blasts, therapeutic approaches to AML now feature the approved antibody drug conjugate (Mylotarg, GO) and investigational CART cell approaches incorporating CD33-binding domains derived from humanized scFvs. We designed a functional chimeric antigen receptor utilizing a human targeting sequence, derived from a heavy chain variable domain, termed CAR33VH. Lentiviral-based expression vectors which encoded CAR constructs incorporating the novel binding domain (CAR33VH), or the My96 scFv control binder (My96CAR) in frame with a CD8 hinge and transmembrane domain, a 4-1BB costimulatory domain and a CD3 zeta activation domain, were transduced into primary human CD4+ and CD8+ T cells, and CAR expression was confirmed by flow cytometry...
2018: Frontiers in Oncology
Juan M Zapata, Gema Perez-Chacon, Pablo Carr-Baena, Ivan Martinez-Forero, Arantza Azpilikueta, Itziar Otano, Ignacio Melero
CD137 (4-1BB, Tnsfr9) is a member of the TNF-receptor (TNFR) superfamily without known intrinsic enzymatic activity in its cytoplasmic domain. Hence, akin to other members of the TNFR family, it relies on the TNFR-Associated-Factor (TRAF) family of adaptor proteins to build the CD137 signalosome for transducing signals into the cell. Thus, upon CD137 activation by binding of CD137L trimers or by crosslinking with agonist monoclonal antibodies, TRAF1, TRAF2, and TRAF3 are readily recruited to the cytoplasmic domain of CD137, likely as homo- and/or heterotrimers with different configurations, initiating the construction of the CD137 signalosome...
2018: Frontiers in Immunology
Zurong Wan, Xingxing Shao, Xingyu Ji, Lihui Dong, Jiacheng Wei, Zhuqing Xiong, Wanli Liu, Hai Qi
The B7-family inducible costimulator (ICOS) activates phosphoinositide-3 kinase (PI3K) and augments calcium mobilization triggered by the T-cell receptor (TCR). We surprisingly found that the entire cytoplasmic domain of ICOS is dispensable for its costimulation of calcium mobilization. This costimulatory function relies on the unique transmembrane domain (TMD) of ICOS, which promotes association with the tyrosine kinase Lck. TMD-enabled Lck association is also required for p85 recruitment to ICOS and subsequent PI3K activation, and Lck underlies both the bystander and costimulatory signaling activity of ICOS...
December 6, 2018: Cellular & Molecular Immunology
John P Murad, Anna K Kozlowska, Hee Jun Lee, Maya Ramamurthy, Wen-Chung Chang, Paul Yazaki, David Colcher, John Shively, Mihaela Cristea, Stephen J Forman, Saul J Priceman
Impressive clinical efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy for hematological malignancies have prompted significant efforts in achieving similar responses in solid tumors. The lack of truly restricted and uniform expression of tumor-associated antigens, as well as limited T cell persistence and/or tumor trafficking pose major challenges for successful translation of CAR T cell therapy in solid tumors. Recent studies have demonstrated that aberrantly glycosylated cell surface proteins on tumor cells are amenable CAR targets...
2018: Frontiers in Immunology
Michael A Pulsipher
Multicenter trials in children and young adults using second-generation CD19-targeted chimeric antigen receptor (CAR) T cells have shown dramatic levels of remission in patients with multiply relapsed/refractory disease (80% to ≥90%). Early results in adult trials have also shown significant responses, and strategies aimed at mitigating toxicities associated with the therapy have improved tolerability. Therefore, if available, CAR T-cell therapy deserves consideration for salvage of children and adults with B-lineage acute lymphoblastic leukemia (B-ALL) who are multiply relapsed, refractory, or relapsed after a previous allogeneic transplantation...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Hadas Weinstein-Marom, Noam Levin, Aviad Pato, Nofar Shmuel, Adi Sharabi-Nov, Tamar Peretz, Galit Eisenberg, Michal Lotem, Orit Itzhaki, Michal J Besser, Gideon Gross
Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or gene-modified T cells expressing antitumor TCRs or chimeric antigen receptors often yields a high rate of clinical response in several types of cancer. New approaches for enhancing the functional properties of antitumor T cells could improve the clinical outcome of these treatments. To this end, we created 3 classes of genes, each designed to operate autonomously upon expression in T cells. We recently reported on the enhancing effects of constitutively active toll-like receptor 4 (caTLR4), membrane (mem) interleukin-2, memIL-12, and memIL-15, and self-oligomerizing, constitutively active CD40 (caCD40)...
February 2019: Journal of Immunotherapy
Yiyang Xu, Zhiyuan Yang, Lucas H Horan, Pengbo Zhang, Lianxing Liu, Bryan Zimdahl, Shon Green, Jingwei Lu, Javier F Morales, David M Barrett, Stephan A Grupp, Vivien W Chan, Hong Liu, Cheng Liu
The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain...
2018: Cell Discovery
Sushmita Nair, Jing-Bo Wang, Shih-Ting Tsao, Yuchen Liu, Wei Zhu, William B Slayton, Jan S Moreb, Lujia Dong, Lung-Ji Chang
Recent studies of CD19-specific chimeric antigen receptor (CAR)-modified T cells (CARTs) have demonstrated unprecedented successes in treating refractory and relapsed B cell malignancies. The key to the latest CART therapy advances can be attributed to the improved co-stimulatory signals in the CAR design. Here we established several novel CARs by incorporating T cell signaling domains of CD28 in conjunction with intracellular signaling motif of 4-1BB, CD27, OX40, ICOS, and IL-15Rα. These novel CARs were functionally assessed based on a simple target cell killing assay...
November 15, 2018: Current Gene Therapy
Hamid Reza Mirzaei, Arezoo Jamali, Leila Jafarzadeh, Elham Masoumi, Khadijeh Alishah, Keyvan Fallah Mehrjardi, Seyed Amir Hossein Emami, Farshid Noorbakhsh, Brian G Till, Jamshid Hadjati
Although remarkable results have been attained by adoptively transferring T cells expressing fully murine and/or humanized anti-CD19 chimeric antigen receptors (CARs) to treat B cell malignancies, evidence of human anti-mouse immune responses against CARs provides a rationale for the development of less immunogenic CARs. By developing a fully human CAR (huCAR), these human anti-mouse immune responses are likely eliminated. This, perhaps, not only increases the persistence of anti-CD19 CAR T cells-thereby reducing the risk of tumor relapse-but also facilitates administration of multiple, temporally separated doses of CAR T cells to the same recipient...
October 26, 2018: Journal of Cellular Physiology
Xingliang Guo, Hua Jiang, Bizhi Shi, Min Zhou, Honghong Zhang, Zhimin Shi, Guoxiu Du, Hong Luo, Xiuqi Wu, Yi Wang, Ruixin Sun, Zonghai Li
Cancer immunotherapy has made unprecedented breakthrough in the fields of chimeric antigen receptor-redirected T (CAR T) cell therapy and immune modulation. Combination of CAR modification and the disruption of endogenous inhibitory immune checkpoints on T cells represent a promising immunotherapeutic modality for cancer treatment. However, the potential for the treatment of hepatocellular carcinoma (HCC) has not been explored. In this study, the gene expressing the programmed death 1 receptor (PD-1) on the Glypican-3 (GPC3)-targeted second-generation CAR T cells employing CD28 as the co-stimulatory domain was disrupted using the CRISPR/Cas9 gene-editing system...
2018: Frontiers in Pharmacology
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