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Chimeric antigen therapy

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https://www.readbyqxmd.com/read/27913530/cytokine-release-syndrome-with-novel-therapeutics-for-acute-lymphoblastic-leukemia
#1
Noelle V Frey, David L Porter
T-cell-engaging immunotherapies are exciting new approaches to treat patients with acute lymphoblastic leukemia (ALL). These unique agents, which include blinatumomab, a CD3/CD19 bispecific antibody, and chimeric antigen receptor (CAR) modified T cells targeted to CD19 have shown unprecedented remission rates in the relapsed, refractory ALL setting. Cytokine release syndrome (CRS), resulting from the high magnitude of immune activation by these therapies, is the most significant treatment-related toxicity. CRS manifests with fever and malaise and can progress to life-threatening capillary leak with hypoxia and hypotension...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913524/cellular-and-vaccine-immunotherapy-for-multiple-myeloma
#2
Alfred L Garfall, Edward A Stadtmauer
Allogeneic hematopoietic cell transplantation and donor lymphocyte infusion for multiple myeloma (MM) can induce graft-versus-myeloma immunity and long-term survivorship, but limited efficacy and associated toxicities have prevented its widespread use. Cellular immunotherapies and vaccines seek to induce more specific, reliable, and potent antimyeloma immune responses with less treatment-related risk than is possible with allogeneic transplantation. Advances in molecular biology, and basic and applied immunology, have led to promising approaches such as genetically engineered T cells with chimeric antigen receptors and T-cell receptors targeting myeloma-specific epitopes, vaccine primed ex vivo expanded autologous T cells, expanded marrow-infiltrating lymphocytes, and plasma cell/dendritic cell fusion vaccines...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27910858/immunosuppression-in-liver-tumors-opening-the-portal-to-effective-immunotherapy
#3
REVIEW
P Guha, J Reha, S C Katz
We have recently witnessed substantial progress with immunotherapy for selected diseases. Checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cells are among the most promising agents. Whereas much of the early success with CAR-T cells has been demonstrated with hematological malignancies, important barriers remain for the application of CAR-T cell therapies for the management of metastatic solid tumors. The challenges are particularly apparent when considering primary and metastatic tumors in the liver...
December 2, 2016: Cancer Gene Therapy
https://www.readbyqxmd.com/read/27907215/cd8-t-cells-induce-fatal-brainstem-pathology-during-cerebral-malaria-via-luminal-antigen-specific-engagement-of-brain-vasculature
#4
Phillip A Swanson, Geoffrey T Hart, Matthew V Russo, Debasis Nayak, Takele Yazew, Mirna Peña, Shahid M Khan, Chris J Janse, Susan K Pierce, Dorian B McGavern
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27907031/in-vitro-pre-clinical-validation-of-suicide-gene-modified-anti-cd33-redirected-chimeric-antigen-receptor-t-cells-for-acute-myeloid-leukemia
#5
Kentaro Minagawa, Muhammad O Jamil, Mustafa Al-Obaidi, Larisa Pereboeva, Donna Salzman, Harry P Erba, Lawrence S Lamb, Ravi Bhatia, Shin Mineishi, Antonio Di Stasi
BACKGROUND: Approximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia...
2016: PloS One
https://www.readbyqxmd.com/read/27905838/engineering-hiv-specific-immunity-with-chimeric-antigen-receptors
#6
Scott G Kitchen, Jerome A Zack
HIV remains a highly important public health and clinical issue despite many recent advances in attempting to develop a cure, which has remained elusive for most people infected with HIV. HIV disease can be controlled with pharmacologic therapies; however, these treatments are expensive, may have severe side effects, and are not curative. Consequently, an improved means to control or eliminate HIV replication is needed. Cytotoxic T lymphocytes (CTLs) play a critical role in controlling viral replication and are an important part in the ability of the immune response to eradicate most viral infections...
December 2016: AIDS Patient Care and STDs
https://www.readbyqxmd.com/read/27897048/a-rapid-cell-expansion-process-for-production-of-engineered-autologous-car-t-cell-therapies
#7
Tangying Lily Lu, Omar Pugach, Robert P T Somerville, Steven A Rosenberg, James N Kochenderfer, Marc Better, Steven A Feldman
The treatment of B cell malignancies by adoptive cell transfer (ACT) of anti-CD19 chimeric antigen receptor T cells (CD19 CAR-T) has proven to be a highly successful therapeutic modality in several clinical trials<sup>1-6</sup>. The anti-CD19 CAR T cell production method used to support initial trials relied on numerous manual, open process steps, cell culture media supplemented with human serum and 10 days of cell culture to achieve a clinical dose <sup>7</sup>. This approach limited the ability to support large multicenter clinical trials, as well as scale-up for commercial cell production...
November 29, 2016: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/27895644/recent-developments-in-cellular-immunotherapy-for-hsct-associated-complications
#8
REVIEW
Monica Reis, Justyna Ogonek, Marsela Qesari, Nuno M Borges, Lindsay Nicholson, Liane Preußner, Anne Mary Dickinson, Xiao-Nong Wang, Eva M Weissinger, Anne Richter
Allogeneic hematopoietic stem cell transplantation is associated with serious complications, and improvement of the overall clinical outcome of patients with hematological malignancies is necessary. During the last decades, posttransplant donor-derived adoptive cellular immunotherapeutic strategies have been progressively developed for the treatment of graft-versus-host disease (GvHD), infectious complications, and tumor relapses. To date, the common challenge of all these cell-based approaches is their implementation for clinical application...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27890255/chimeric-antigen-receptor-t-cell-therapy-in-aml-how-close-are-we
#9
REVIEW
Saar Gill
The majority of patients presenting with acute myeloid leukemia (AML) initially respond to chemotherapy but post-remission therapy is required to consolidate this response and achieve long-term disease-free survival. The most effective form of post-remission therapy relies on T cell immunotherapy in the form of allogeneic hematopoietic cell transplantation (HCT). However, patients with active disease cannot usually expect to be cured with HCT. This inherent dichotomy implies that traditional T cell-based immunotherapy in the form of allogeneic HCT stops being efficacious somewhere between the measurable residual disease (MRD) and the morphologically obvious range...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27889981/chimeric-trojan-protein-insertion-in-lentiviral-membranes-makes-lentiviruses-susceptible-to-neutralisation-by-anti-tetanus-serum-antibodies
#10
Anita Le-Heron, Steve Patterson, Rafael J Yáñez-Muñoz, George Dickson
This study describes the initial testing of a novel strategy for neutralisation of lentiviruses using the fundamental biology of enveloped viruses' assembly and budding. In the field of gene therapy, viral vector surface proteins have been manipulated in order to redirect host cell specificity by alteration of pseudo-types. We tested whether known viral pseudo-typing proteins or surface proteins known to be recruited to the HIV envelope could be engineered to carry neutralising epitopes from another microorganism onto the lentiviral surface...
November 27, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27887660/co-infusion-of-haplo-identical-cd19-chimeric-antigen-receptor-t-cells-and-stem-cells-achieved-full-donor-engraftment-in-refractory-acute-lymphoblastic-leukemia
#11
Bo Cai, Mei Guo, Yao Wang, Yajing Zhang, Jun Yang, Yelei Guo, Hanren Dai, Changlin Yu, Qiyun Sun, Jianhui Qiao, Kaixun Hu, Hongli Zuo, Zheng Dong, Zechuan Zhang, Mingxing Feng, Bingxia Li, Yujing Sun, Tieqiang Liu, Zhiqing Liu, Yi Wang, Yajing Huang, Bo Yao, Weidong Han, Huisheng Ai
BACKGROUND: Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T) cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined. CASE PRESENTATION: We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC) following induction chemotherapy...
November 25, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27882353/longitudinal-pet-imaging-demonstrates-biphasic-car-t-cell-responses-in-survivors
#12
Yogindra Vedvyas, Enda Shevlin, Marjan Zaman, Irene M Min, Alejandro Amor-Coarasa, Spencer Park, Susan Park, Keon-Woo Kwon, Turner Smith, Yonghua Luo, Dohyun Kim, Young Kim, Benedict Law, Richard Ting, John Babich, Moonsoo M Jin
Clinical monitoring of adoptive T cell transfer (ACT) utilizes serial blood analyses to discern T cell activity. While useful, these data are 1-dimensional and lack spatiotemporal information related to treatment efficacy or toxicity. We utilized a human genetic reporter, somatostatin receptor 2 (SSTR2), and PET, to quantitatively and longitudinally visualize whole-body T cell distribution and antitumor dynamics using a clinically approved radiotracer. Initial evaluations determined that SSTR2-expressing T cells were detectable at low densities with high sensitivity and specificity...
November 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27875673/recent-advances-in-engineered-t-cell-therapies-targeting-b-cell-malignancies
#13
Nathan Singh
Immunotherapy using engineered autologous T cells has been attempted for decades, but clinical trials have only recently demonstrated efficacy. The combination of enhanced manufacturing techniques, highly efficient engineering, appropriate target selection and synthetic receptors with potent T cell activating domains has led to the development of highly-active cellular therapy products. B-cell malignancies have served as the paradigmatic diseases to initially evaluate and subsequently hone engineered T cells targeting cancer...
October 2016: Discovery Medicine
https://www.readbyqxmd.com/read/27870103/role-of-immunotherapy-in-targeting-the-bone-marrow-microenvironment-in-multiple-myeloma-an-evolving-therapeutic-strategy
#14
Clement Chung
Multiple myeloma (referred to henceforth as myeloma) is a B-cell malignancy characterized by unregulated growth of plasma cells in the bone marrow. The treatment paradigm for myeloma underwent significant evolution in the last decade, with an improved understanding of the pathogenesis of the disease as well as the development of therapeutic agents that target not only the tumor cells but also their microenvironment. Despite these therapeutic advances, the prognosis of patients with relapsed or refractory myeloma remains poor...
November 21, 2016: Pharmacotherapy
https://www.readbyqxmd.com/read/27865176/adoptive-immunotherapy-for-hematological-malignancies-current-status-and-new-insights-in-chimeric-antigen-receptor-t-cells
#15
REVIEW
Alessandro Allegra, Vanessa Innao, Demetrio Gerace, Doriana Vaddinelli, Caterina Musolino
Hematological malignancies frequently express cancer-associated antigens that are shared with normal cells. Such tumor cells elude the host immune system because several T cells targeted against self-antigens are removed during thymic development, and those that persist are eliminated by a regulatory population of T cells. Chimeric antigen receptor-modified T cells (CAR-Ts) have emerged as a novel modality for tumor immunotherapy due to their powerful efficacy against tumor cells. These cells are created by transducing genes-coding fusion proteins of tumor antigen-recognition single-chain Fv connected to the intracellular signaling domains of T cell receptors, and are classed as first-, second- and third-generation, differing on the intracellular signaling domain number of T cell receptors...
November 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/27863374/magic-year-for-multiple-myeloma-therapeutics-key-takeaways-from-the-ash-2015-annual-meeting
#16
REVIEW
Kejie Zhang, Aakash Desai, Dongfeng Zeng, Tiejun Gong, Peihua Lu, Michael Wang
Despite the availability of various anticancer agents, Multiple Myeloma (MM) remains incurable in most cases, along with high relapse rate in the patients treated with these agents. The year 2015 saw major advancements in our battle against multiple myeloma. In 2015, the U.S. Food and Drug Administration (FDA) approved three new therapies for multiple myeloma, namely Ixazomib (an oral proteasome inhibitor), Daratumumab and Elotuzumab (monoclonal antibodies against CD38 and SLAMF7 respectively). The purpose of this review is to provide a detailed analysis of these aforementioned breakthrough therapies and two other newer agents, Filanesib (kinesis spindle inhibitor) and selinexor (SINE inhibitor), presented at the 2015 annual meeting of American Society of Hematology (ASH)...
November 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27863199/mesothelin-immunotherapy-for-cancer-ready-for-prime-time
#17
Raffit Hassan, Anish Thomas, Christine Alewine, Dung T Le, Elizabeth M Jaffee, Ira Pastan
Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies...
December 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27860544/car-t-cell-therapy-for-solid-tumors
#18
Kheng Newick, Shaun O'Brien, Edmund Moon, Steven M Albelda
The field of cancer immunotherapy has been re-energized by the application of chimeric antigen receptor (CAR) T cell therapy in cancers. These CAR T cells are engineered to express synthetic receptors that redirect polyclonal T cells to surface antigens for subsequent tumor elimination. Many CARs are designed with elements that augment T cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematologic malignancies (e.g., CD19 CARs in leukemias). However, this success has yet to be extrapolated to solid tumors, and the reasons for this are being actively investigated...
November 17, 2016: Annual Review of Medicine
https://www.readbyqxmd.com/read/27855281/car-t-therapy-for-leukemia-progress-and-challenges
#19
REVIEW
Xin Wang, Qing Xiao, Zhe Wang, Wen-Li Feng
Despite the rapid development of therapeutic strategies, leukemia remains a type of difficult-to-treat hematopoietic malignancy that necessitates introduction of more effective treatment options to improve life expectancy and quality of patients. Genetic engineering in adoptively transferred T cells to express antigen-specific chimeric antigen receptors (CARs) has proved highly powerful and efficacious in inducing sustained responses in patients with refractory malignancies, as exemplified by the success of CD19-targeting CAR-T treatment in patients with relapsed acute lymphoblastic leukemia...
October 27, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/27853651/gucy2c-directed-car-t-cells-oppose-colorectal-cancer-metastases-without-autoimmunity
#20
Michael S Magee, Crystal L Kraft, Tara S Abraham, Trevor R Baybutt, Glen P Marszalowicz, Peng Li, Scott A Waldman, Adam E Snook
Adoptive T-cell therapy (ACT) is an emerging paradigm in which T cells are genetically modified to target cancer-associated antigens and eradicate tumors. However, challenges treating epithelial cancers with ACT reflect antigen targets that are not tumor-specific, permitting immune damage to normal tissues, and preclinical testing in artificial xenogeneic models, preventing prediction of toxicities in patients. In that context, mucosa-restricted antigens expressed by cancers exploit anatomical compartmentalization which shields mucosae from systemic antitumor immunity...
2016: Oncoimmunology
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