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Nan Chen, Xiaoyu Li, Navin K Chintala, Zachary E Tano, Prasad S Adusumilli
Uniform and strong expression of CD19, a cell surface antigen, on cells of B-cell lineage is unique to hematologic malignancies. Tumor-associated antigen (TAA) targets in solid tumors exhibit heterogeneity with regards to intensity and distribution, posing a challenge for chimeric antigen receptor (CAR) T-cell therapy. Novel CAR designs, such as dual TAA-targeted CARs, tandem CARs, and switchable CARs, in conjunction with inhibitory CARs, are being investigated as means to overcome antigen heterogeneity. In addition to heterogeneity in cancer-cell antigen expression, the key determinants for antitumor responses are CAR expression levels and affinity in T cells...
March 16, 2018: Current Opinion in Immunology
Li-Na Zhang, Yongping Song, Delong Liu
The prognosis of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) remains dismal even at this day and age. With salvage chemotherapy, only 29% (range 18 to 44%) of the patients with R/R ALL can be induced into complete remission (CR), with a median overall survival (OS) of 4 months (range 2-6 months). Blinatumomab and inotuzumab ozogamycin (IO) are immunotherapeutic agents that increased CR to 80% and extended survival to 7.7 months in this high-risk population of patients. In the last few years, chimeric antigen receptor (CAR)--engineered T cells have led to major progress in cancer immunotherapy...
March 15, 2018: Journal of Hematology & Oncology
Nia Emami-Shahri, Julie Foster, Roxana Kashani, Patrycja Gazinska, Celia Cook, Jane Sosabowski, John Maher, Sophie Papa
The unprecedented efficacy of chimeric antigen receptor (CAR) T-cell immunotherapy of CD19+ B-cell malignancy has established a new therapeutic pillar of hematology-oncology. Nonetheless, formidable challenges remain for the attainment of comparable success in patients with solid tumors. To accelerate progress and rapidly characterize emerging toxicities, systems that permit the repeated and non-invasive assessment of CAR T-cell bio-distribution would be invaluable. An ideal solution would entail the use of a non-immunogenic reporter that mediates specific uptake of an inexpensive, non-toxic and clinically established imaging tracer by CAR T cells...
March 14, 2018: Nature Communications
Lisa M Ebert, Wenbo Yu, Tessa Gargett, Michael P Brown
Chimeric antigen receptor (CAR)-T cell therapy has been clinically validated as a curative treatment for the difficult to treat malignancies of relapsed/refractory B-cell acute lymphoblastic leukaemia and lymphoma. Here, the CAR-T cells are re-directed towards a single antigen, CD19, which is recognised as a virtually ideal CAR target antigen because it has strong, uniform expression on cancer cells, and is otherwise expressed only on healthy B cells, which are 'dispensable'. Notwithstanding the clinical success of CD19-CAR-T cell therapy, its single specificity has driven therapeutic resistance in 30% or more of cases with CD19-negative leukaemic relapses...
March 14, 2018: Biochemical Society Transactions
Shinichi Kageyama
Cancer immunotherapies using gene-engineered T cells comprise adoptive transfer of T-cell receptor (TCR) and chimeric antigen receptor (CAR) gene-transduced T cells. Although CD19-targeting CAR-T cell therapy is the most progressed, wherein B-cell malignancy is treated efficiently, it also induces cytokine release syndrome and neurotoxicity, which frequently leads to serious adverse events. Of note, TCR-T cell therapy has been primarily used to target melanoma, resulting in 30%-50% of tumor responses. In clinical trials that target NY-ESO-1-expressing synovial sarcoma, a high efficacy of 50%-60% has been obtained...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Takahiro Kamiya, Desmond Wong, Yi Tian Png, Dario Campana
Practical methods are needed to increase the applicability and efficacy of chimeric antigen receptor (CAR) T-cell therapies. Using donor-derived CAR-T cells is attractive, but expression of endogenous T-cell receptors (TCRs) carries the risk for graft-versus-host-disease (GVHD). To remove surface TCRαβ, we combined an antibody-derived single-chain variable fragment specific for CD3ε with 21 different amino acid sequences predicted to retain it intracellularly. After transduction in T cells, several of these protein expression blockers (PEBLs) colocalized intracellularly with CD3ε, blocking surface CD3 and TCRαβ expression...
March 13, 2018: Blood Advances
Zhi Cheng, Runhong Wei, Qiuling Ma, Lin Shi, Feng He, Zixiao Shi, Tao Jin, Ronglin Xie, Baofeng Wei, Jing Chen, Hongliang Fang, Xiaolu Han, Jennifer A Rohrs, Paul Bryson, Yarong Liu, Qi-Jing Li, Bo Zhu, Pin Wang
Several recent clinical trials have successfully incorporated a costimulatory domain derived from either CD28 or 4-1BB with the original CD3ζ T cell activating domain to form second-generation chimeric antigen receptors (CARs) that can increase the responsiveness and survival of CAR-engineered T (CAR-T) cells. However, a rigorous assessment of the individual benefits of these costimulatory components relative to the in vivo performance of infused T cells in patients is still lacking. Therefore, we have designed a study that allows us to investigate and compare the impact of different costimulatory signal domains on CAR-T cells in vivo...
February 2, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Ping-Pin Zheng, Johan M Kros, Jin Li
Two autologous chimeric antigen receptor (CAR) T cell therapies (Kymriah™ and Yescarta™) were recently approved by the FDA. Kymriah™ for the treatment of pediatric patients and young adults with refractory or relapse (R/R) B cell precursor acute lymphoblastic leukemia and Yescarta™ for the treatment of adult patients with R/R large B cell lymphoma. In common, both drugs are CD19-specific CAR T cell therapies lysing CD19-positive targets. Their dramatic efficacy in the short term has been highlighted by many media reports...
March 1, 2018: Drug Discovery Today
David Porter, Noelle Frey, Patricia A Wood, Yanqiu Weng, Stephan A Grupp
BACKGROUND: Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions. DISCUSSION: The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy...
March 2, 2018: Journal of Hematology & Oncology
Karlo Perica, Kevin J Curran, Renier J Brentjens, Sergio A Giralt
Two commercial Chimeric Antigen Receptor (CAR) T cell therapies for CD19 expressing B cell malignancies, Kymriah and Yescarta, have recently been approved by the FDA. The administration of CAR T cells is a complex endeavor involving cell manufacture, tracking and shipping of apheresis products, and management of novel and severe toxicities. At Memorial Sloan Kettering Cancer Center, we have identified eight essential tasks that define the CAR T cell workflow. In this review, we discuss practical aspects of CAR T cell program development, including clinical, administrative, and regulatory challenges for successful implementation...
February 27, 2018: Biology of Blood and Marrow Transplantation
Rohtesh S Mehta, Katayoun Rezvani
Adoptive cell therapy has emerged as a powerful treatment for advanced cancers resistant to conventional agents. Most notable are the remarkable responses seen in patients receiving autologous CD19-redirected chimeric antigen receptor (CAR) T cells for the treatment of B lymphoid malignancies; however, the generation of autologous products for each patient is logistically cumbersome and has restricted widespread clinical use. A banked allogeneic product has the potential to overcome these limitations, yet allogeneic T-cells (even if human leukocyte antigen-matched) carry a major risk of graft-versus-host disease (GVHD)...
2018: Frontiers in Immunology
Dominik Bachmann, Roberta Aliperta, Ralf Bergmann, Anja Feldmann, Stefanie Koristka, Claudia Arndt, Simon Loff, Petra Welzel, Susann Albert, Alexandra Kegler, Armin Ehninger, Marc Cartellieri, Gerhard Ehninger, Martin Bornhäuser, Malte von Bonin, Carsten Werner, Jens Pietzsch, Jörg Steinbach, Michael Bachmann
Recent treatments of leukemias with T cells expressing chimeric antigen receptors (CARs) underline their impressive therapeutic potential but also their risk of severe side effects including cytokine release storms and tumor lysis syndrome. In case of cross-reactivities, CAR T cells may also attack healthy tissues. To overcome these limitations, we previously established a switchable CAR platform technology termed UniCAR. UniCARs are not directed against typical tumor-associated antigens (TAAs) but instead against a unique peptide epitope: Fusion of this peptide epitope to a recombinant antibody domain results in a target module (TM)...
January 26, 2018: Oncotarget
Jae H Park, F Andres Romero, Ying Taur, Michel Sadelain, Renier J Brentjens, Tobias M Hohl, Susan K Seo
Background: Chimeric antigen receptor (CAR)-modified T cells that target the CD19 antigen present a novel promising therapy for the treatment of relapsed B-cell acute lymphoblastic leukemia (ALL). Although cytokine release syndrome (CRS) and neurotoxicity have emerged as predominant non-infectious complications of CD19 CAR T cell therapy, infections associated with this treatment modality have not been well documented. Methods: We analyzed infectious complications that followed CD19 CAR T cell therapy in 53 adult patients with relapsed ALL enrolled in a phase I clinical trial at Memorial Sloan Kettering Cancer Center (NCT01044069)...
February 22, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Pavlína Ptáčková, Jan Musil, Martin Štach, Petr Lesný, Šárka Němečková, Vlastimil Král, Milan Fábry, Pavel Otáhal
BACKGROUND AIMS: Clinical-grade chimeric antigenic receptor (CAR)19 T cells are routinely manufactured by lentiviral/retroviral (LV/RV) transduction of an anti-CD3/CD28 activated T cells, which are then propagated in a culture medium supplemented with interleukin (IL)-2. The use of LV/RVs for T-cell modification represents a manufacturing challenge due to the complexity of the transduction approach and the necessity of thorough quality control. METHODS: We present here a significantly improved protocol for CAR19 T-cell manufacture that is based on the electroporation of peripheral blood mononuclear cells with plasmid DNA encoding the piggyBac transposon/transposase vectors and their cultivation in the presence of cytokines IL-4, IL-7 and IL-21...
February 20, 2018: Cytotherapy
Vincent Yi Sheng Oei, Marta Siernicka, Agnieszka Graczyk-Jarzynka, Hanna Julie Hoel, Weiwen Yang, Daniel Palacios, Hilde Almasbak, Malgorzata Bajor, Dennis Clement, Ludwig Brandt, Bjorn Onfelt, Jodie Goodridge, Magdalena Winiarska, Radoslaw Zagozdzon, Johanna Olweus, Jon-Amund Kyte, Karl-Johan Malmberg
Natural Killer (NK) cells hold potential as a source of allogeneic cytotoxic effector cells for chimeric antigen receptor (CAR)-mediated therapies. Here, we explored the feasibility of transfecting CAR-encoding mRNA into primary NK cells and investigated how the intrinsic potential of discrete NK-cell subsets affects retargeting efficiency. After screening five 2nd- and 3rd-generation anti-CD19 CAR constructs with different signaling domains and spacer regions, a 3rd-generation CAR with the CH2-domain removed was selected based on its expression and functional profiles...
February 19, 2018: Cancer Immunology Research
Jianyu Weng, Peilong Lai, Le Qin, Yunxin Lai, Zhiwu Jiang, Chenwei Luo, Xin Huang, Suijing Wu, Dan Shao, Chengxin Deng, Lisi Huang, Zesheng Lu, Maohua Zhou, Lingji Zeng, Dongmei Chen, Yulian Wang, Xiaomei Chen, Suxia Geng, Weinkove Robert, Zhaoyang Tang, Chang He, Peng Li, Xin Du
BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promise in the treatment of B cell acute lymphocytic leukemia (B-ALL). However, its efficacy in B-ALL patients with extramedullary involvement is limited due to poor responses and neurotoxicity. Here, we utilized a third generation of CAR T cell vector, which contains the Toll/interleukin-1 receptor (ITR) domain of Toll-like receptor 2 (TLR2), to generate 1928zT2 T cells targeting CD19, and evaluated the efficacy of 1928zT2 T cells in relapse or refractory B-ALL patients with extramedullary involvement...
February 20, 2018: Journal of Hematology & Oncology
Y Liu, X Chen, W Han, Y Zhang
On August 30, 2017, the U.S. Food and Drug Administration (FDA) approved Novartis' tisagenlecleucel (CTL-019, Kymriah), which is a synthetic bioimmune product of anti-CD19 chimeric antigen receptor (CAR) T cells, for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). This was a milestone in tumor immunology on account of the significant antitumor effect of tisagenlecleucel for the treatment of relapsed/refractory B-ALL patients. Conventional standard therapies for B-ALL have high failure rates, thus developing new therapies is crucial for patients with B-ALL...
November 2017: Drugs of Today
Lijuan Ding, Yongxian Hu, Kui Zhao, Guoqing Wei, Wenjun Wu, Zhao Wu, Lei Xiao, He Huang
RATIONALE: Cytokine release syndrome (CRS) is a common and potentially fatal complication of CAR-T cell therapy. However, compartment CRS is relatively rare in hematological malignancies, as well as in solid tumors. The pathogenesis and prognosis of compartment CRS are unclear and there is no standardized treatment yet. In this case report, we will introduce a patient developing pleural cavity CRS after CART19s infusion. PATIENT CONCERNS: A 28-year-old woman was admitted for evaluation of mediastinal mass...
February 2018: Medicine (Baltimore)
Jian Li, Wenwen Li, Kejia Huang, Yang Zhang, Gary Kupfer, Qi Zhao
Recently, the US Food and Drug Administration (FDA) approved the first chimeric antigen receptor T cell (CAR-T) therapy for the treatment CD19-positive B cell acute lymphoblastic leukemia. While CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies, whether it can benefit solid tumor patients to the same extent is still uncertain. Even though hundreds of clinical trials are undergoing exploring a variety of tumor-associated antigens (TAA), no such antigen with comparable properties like CD19 has yet been identified regarding solid tumors CAR-T immunotherapy...
February 13, 2018: Journal of Hematology & Oncology
Niaz Muhammad, Qinwen Mao, Haibin Xia
Chimeric antigen receptor (CAR) T-cells are redirected T-cells that can recognize cancer antigens in a major histocompatibility complex (MHC)-independent fashion. A typical CAR is comprised of two main functional domains: an extracellular antigen recognition domain, called a single-chain variable fragment (scFv), and an intracellular signaling domain. Based on the number of intracellular signaling molecules, CARs are categorized into four generations. CAR T-cell therapy has become a promising treatment for hematologic malignancies...
February 12, 2018: Biotechnology & Genetic Engineering Reviews
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