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CAR immune therapy

Jiasheng Wang, Yongxian Hu, Shuye Yang, Guoqin Wei, Xin Zhao, Wenjun Wu, Yanlei Zhang, Yafei Zhang, Donghe Chen, Zhao Wu, Lei Xiao, Alex Hongsheng Chang, He Huang, Kui Zhao
BACKGROUND: CD19-targeting chimeric antigen receptor (CAR) T cell therapy has shown great efficacy in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), but has been associated with serious adverse effects such as cytokine release syndrome (CRS). It has been speculated that NHL baseline disease burden might affect clinical outcome and CRS, but such assumption has not been explored in detail. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as measured by FDG PET-CT, are quantitative indicators of baseline tumor burden...
February 12, 2019: Biology of Blood and Marrow Transplantation
Jürgen Scheller, Erika Engelowski, Jens M Moll, Doreen M Floss
Cytokines control immune-related events and are critically involved in a plethora of physiological and pathophysiological processes including autoimmunity and cancer development. Accordingly, modulation of natural cytokine signaling by antibodies and small molecules has improved therapeutic regimens. Synthetic biology sets out to optimize immunotherapeutics, with chimeric antigen receptor (CAR) T cell immmunotherapy being the first example to combine synthetic biology with genetic engineering during therapy...
February 6, 2019: Trends in Immunology
Wassim Mchayleh, Prabhjot Bedi, Rajesh Sehgal, Melhem Solh
The immune system acting via cancer immune-surveillance is considered a potential target for improving outcomes among some malignancies. The ability to harness immune cells, engineer them and educate them to target cancer cells has changed the paradigm for treating non-Hodgkin's lymphomas (NHL) and acute lymphoblastic leukemia (ALL). Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable anti-tumor activity against refractory B cell malignancies. Ongoing research aims to expand the scope of this adoptive cell therapy, understanding mechanisms of resistance and reducing toxicity...
February 7, 2019: Journal of Clinical Medicine
Yuta Ando, Elizabeth L Siegler, Hoang P Ta, Gunce E Cinay, Hao Zhou, Kimberly A Gorrell, Hannah Au, Bethany M Jarvis, Pin Wang, Keyue Shen
Despite its revolutionary success in hematological malignancies, chimeric antigen receptor T (CAR-T) cell therapy faces disappointing clinical results in solid tumors. The poor efficacy has been partially attributed to the lack of understanding in how CAR-T cells function in a solid tumor microenvironment. Hypoxia plays a critical role in cancer progression and immune editing, which potentially results in solid tumors escaping immunosurveillance and CAR-T cell-mediated cytotoxicity. Mechanistic studies of CAR-T cell biology in a physiological environment has been limited by the complexity of tumor-immune interactions in clinical and animal models, as well as by a lack of reliable in vitro models...
February 8, 2019: Advanced Healthcare Materials
Kirk D Wyatt, Richard J Bram
Advances in multi-agent chemotherapy and supportive care have dramatically improved survival of children with B-cell acute lymphoblastic leukemia (B-ALL); however, patients with relapsed and refractory disease continue to represent a therapeutic challenge. Hematopoietic stem cell transplant was the first immunotherapeutic approach to be used in the treatment of patients with relapsed or refractory disease. However, novel therapies such as bispecific antibodies that engage T-cells and chimeric antigen receptor T-cells (CAR-T) therapy have emerged as novel FDA-approved options that have the potential to become the new standard of care for these difficult-to-treat leukemias...
February 1, 2019: Human Immunology
Ming Liu, Fukun Guo
Traditional cancer therapies include surgery, radiation, and chemotherapy, all of which are typically non-specific approaches. Cancer immunotherapy is a type of cancer treatment that helps the immune system fight cancer. Cancer immunotherapy represents a standing example of precision medicine: immune checkpoint inhibitors precisely target the checkpoints; tumor infiltrating lymphocytes, TCR T cells, and CAR T cells precisely kill cancer cells through tumor antigen recognition; and cancer vaccines are made from patient-derived dendritic cells, tumor cell DNA, or RNA, or oncolytic viruses, thus offering a type of personalized medicine...
September 2018: Precision clinical medicine
Angelika L Erwin, Robert J Desnick
Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by photosensitivity and by hematologic abnormalities in affected individuals. CEP is caused by mutations in the uroporphyrinogen synthase (UROS) gene. In three reported cases, CEP has been associated with a specific X-linked GATA1 mutation. Disease-causing mutations in either gene result in absent or markedly reduced UROS enzymatic activity. This in turn leads to the accumulation of the non-physiologic and photoreactive porphyrinogens, uroporphyrinogen I and coproporphyrinogen I, which damage erythrocytes and elicit a phototoxic reaction upon light exposure...
December 27, 2018: Molecular Genetics and Metabolism
Anna Schurich, Isabelle Magalhaes, Jonas Mattsson
The field of immunometabolism has attracted growing attention as an area at the heart of immune regulation. Upon activation, T cells undergo significant metabolic changes allowing them to mediate effector responses. The advent of chimeric antigen receptor T cell-adoptive therapy has shown some striking clinical efficacy but fails to induce sufficient antitumor response in many patients. Solid tumors put up significant opposition creating a microenvironment deficient of oxygen and glucose, depriving T cells of energy and pushing them to exhaustion...
March 2019: Immunotherapy
Myo Htut
PURPOSE OF REVIEW: The treatment landscape for multiple myeloma has evolved rapidly with the availability of multiple new drugs; however, although patient survival has improved, the disease remains incurable. Multiple myeloma is characterized by the unregulated growth of malignant plasma cells accompanied by immune dysfunction as well as disrupted immune surveillance mechanisms. Here, we analyze clinical modalities, with a focus on monoclonal antibodies and adoptive cellular therapy that enhance patients' immune systems and overcome these defects...
January 21, 2019: Current Hematologic Malignancy Reports
Saikat Ghosh, Rohan Lalani, Vivek Patel, Denish Bardoliwala, Kuntal Maiti, Shubhadeep Banerjee, Subhas Bhowmick, Ambikanandan Misra
Hematological cancers are a group of malignancies affecting human hematopoietic and lymphoid tissues. Although the patients respond to treatment regimen during initial phases, the hematoma tumor heterogeneity results in the presence of some minimal disease residue thereby exhibiting remission, relapses or refractoriness in disease conditions leading to poor overall survival period. The current therapeutic standard practices involve blending of conventional agents with novel targeting agents or immune-therapeutics in a cocktail to effectively reap the benefits of drugs acting through multiple signaling pathways...
January 18, 2019: Journal of Controlled Release: Official Journal of the Controlled Release Society
Shan Gao, Dongjuan Yang, Yan Fang, Xiaojie Lin, Xuechao Jin, Qi Wang, Xiyan Wang, Liyuan Ke, Kai Shi
Owing to the fast-paced growth and cross-infiltration of oncology, immunology and molecular biology, tumor immunotherapy technology represented by immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapy has lately made remarkable advancements. In comparison with traditional chemotherapy, immunotherapy has the potential to elicit a stronger sustained antitumor immune response in those patients who have advanced malignant malignancies. In spite of the advancements made, a significant number of clinical research works have validated that an extensive proportion of cancer patients still manifest insensitivity to immunotherapy, primarily because of the immunomodulatory interactions between tumor cells and the immunosuppressive tumor microenvironment (TME), together mediating the immune tolerance of tumors and accordingly impacting the positive response to immunotherapy...
2019: Theranostics
Jitwadee Inthagard, Joanne Edwards, Antonia K Roseweir
Cancer treatments often reach a refractory period leading to treatment failure and patients developing disease recurrence. This can be due to tumour cells escaping the immune response and creating an immunosuppressive microenvironment enhancing cancer progression. Immunotherapy has become a promising tool for cancer treatment as it restores the anti-tumour response of the patient's immune system. Immune checkpoint inhibitors are the most widely studied immunotherapies worldwide and are now approved for multiple cancers...
January 31, 2019: Clinical Science (1979-)
Robin Parihar, Charlotte H Rivas, Mai Huynh, Bilal Omer, Natalia Lapteva, Leonid S Metelitsa, Stephen Gottschalk, Cliona M Rooney
Solid tumors are refractory to cellular immunotherapies in part because they contain suppressive immune effectors such as myeloid‑derived suppressor cells (MDSCs) that inhibit cytotoxic lymphocytes. Strategies to reverse the suppressive tumor microenvironment (TME) should also attract and activate immune effectors with antitumor activity. To address this need, we developed gene‑modified natural killer (NK) cells bearing a chimeric receptor in which the activating receptor NKG2D is fused to the cytotoxic z-chain of the T-cell receptor (NKG2D...
January 16, 2019: Cancer Immunology Research
Michel Ducreux, Thomas Seufferlein, Jean-Luc Van Laethem, Pierre Laurent-Puig, Cristina Smolenschi, David Malka, Valérie Boige, Antoine Hollebecque, Thierry Conroy
Pancreatic cancer is considered to be one of the most aggressive cancers. For unknown reasons, the incidence of pancreatic cancer is slowly rising and so too are mortality rates. Over 75% of patients are diagnosed with locally advanced disease or with metastases; and more than 95% of patients have metastases at diagnosis or will develop metastases during their follow-up. Despite recent improvements in the therapy of pancreatic cancer, initially with demonstration of the activity of the FOLFIRINOX regimen and subsequently the approval of nab-paclitaxel in combination with gemcitabine, prognosis remains poor and the 5-year survival rate is less than 5%...
December 27, 2018: Seminars in Oncology
Lingli Yan, Bainan Liu
The success of chimeric antigen receptor-modified T-cell (CAR-T) therapy for B-cell lymphocyte malignancies targeting CD19 places it in a rapidly growing field in cancer immunotherapy for both hematological and solid tumors. However, the two types of tumor are quite different in the following respects. Solid tumors are characterized by complex vasculatures and matrix barriers that significantly affect T-cell functions and migration. Moreover, various immunosuppressive molecules expressed in the tumor microenvironment can impede T-cell activation, and the high metabolic rate of tumors competitively suppresses the metabolism of immune cells...
2019: OncoTargets and Therapy
Manxue Fu, Liling Tang
BACKGROUND: Chimeric Antigen Receptor (CAR) T cell immunotherapy, as an innovative method for tumor immunotherapy, acquires unprecedented clinical outcomes. Genetic modification not only provides T cells with the antigen-binding function but also endows T cells better immunological functions both in solid and hematological cancer. However, the CAR T cell therapy is not perfect because of several reasons, such as tumor immune microenvironment, and autologous limiting factors of CAR T cells...
January 11, 2019: Recent Patents on Anti-cancer Drug Discovery
Francesco Ceppi, Raffaele Renella, Manuel Diezi, Marc Ansari, Michel A Duchosal, Caroline Arber, Lana Kandalaft, George Coukos, Maja Beck-Popovic
Fighting leukemia using the immune system (antibodies, lymphocytes) is an old idea, which has already been fulfilled in allogeneic bone marrow transplantation. Indeed, the effectiveness of the transplant depends on the action of the donor lymphocytes. To limit the adverse effects on bystander organs (graft-versus-host disease), autologous T cells can be engineered to express synthetic chimeric antigen receptors (CARs) with artificially redirected antigen specificity. Autologous T cells engineered to express a CAR targeting CD19 have shown unprecedented efficacy in clinical trials for relapsed/refractory B-cell leukemias and lymphomas...
January 9, 2019: Revue Médicale Suisse
Hongbing Ma, Swaminathan Padmanabhan Iyer, Simrit Parmar, Yuping Gong
Acute myeloid leukemia (AML) is the most common tumor in adult patients, most of the patients have a poor prognosis even after high-intensity chemotherapy, especially for relapsed, refractory or elderly patients. Therefore, new methods are needed to change the outcomes. In recent years, an increasing number of immune-therapies are emerging where adoptive cell therapy, a special immunotherapy, has become a promising strategy for AML. Here, we review the clinical application and advancement of donor lymphocyte infusion, chimeric-antigen receptor (CAR) T cell therapy, natural killer (NK) cell therapy and dendritic cell vaccination for AML, hopefully providing an overview of clinical aspects of advances in adoptive cell therapy for AML...
January 10, 2019: Leukemia & Lymphoma
Elin Mv Forsberg, Mattias F Lindberg, Henrik Jespersen, Samuel Alsén, Roger Olofsson Bagge, Marco Donia, Inge Marie Svane, Ola Nilsson, Lars Ny, Lisa M Nilsson, Jonas A Nilsson
Chimeric antigen receptors (CAR) can transmit signals akin to those from activated T cell receptors when bound to a cell surface target. CAR expressing T cells against CD19 can cause curative effects in leukemia and lymphoma and is approved for clinical use. However, no CAR-T therapy is currently approved for use in solid tumors. We hypothesize that the resistance of solid tumors to CAR-T can be overcome by similar means as those used to reactivate tumor-infiltrating T lymphocytes (TIL), e.g., by cytokines or immune checkpoint blockade...
January 8, 2019: Cancer Research
Syed Maaz Tariq, Syed Ali Haider, Mohammad Hasan, Amber Tahir, Maria Khan, Arisha Rehan, Anum Kamal
Despite significant advancements, relapses, and persistent malignancies are still a major challenge faced by the oncologists. Immunotherapy has shown remarkable potential in induction of sustained remission in refractory malignancies. Chimeric antigen receptor T-cell (CAR-T) therapy is a newer treatment methodology approved by the Food and Drug Administration (FDA). The chimeric pairing of an antigen receptor with the T-cell receptor (TCR) intracellular signaling domain allows cluster of designation 8 (CD8) cytotoxic T-cells to target cell surface makers independent of major histocompatibility complex (MHC) activation...
October 23, 2018: Curēus
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