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CAR immune therapy

Katharina Fuchs, Yamel Cardona Gloria, Olaf-Oliver Wolz, Franziska Herster, Lokesh Sharma, Carly A Dillen, Christoph Täumer, Sabine Dickhöfer, Zsofia Bittner, Truong-Minh Dang, Anurag Singh, Daniel Haischer, Maria A Schlöffel, Kirsten J Koymans, Tharmila Sanmuganantham, Milena Krach, Thierry Roger, Didier Le Roy, Nadine A Schilling, Felix Frauhammer, Lloyd S Miller, Thorsten Nürnberger, Salomé LeibundGut-Landmann, Andrea A Gust, Boris Macek, Martin Frank, Cécile Gouttefangeas, Charles S Dela Cruz, Dominik Hartl, Alexander Nr Weber
Chitin is the second most abundant polysaccharide in nature and linked to fungal infection and asthma. However, bona fide immune receptors directly binding chitin and signaling immune activation and inflammation have not been clearly identified because polymeric crude chitin with unknown purity and molecular composition has been used. By using defined chitin (N-acetyl-glucosamine) oligomers, we here identify six-subunit-long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll-like receptor (TLR2) as a primary fungal chitin sensor on human and murine immune cells...
October 18, 2018: EMBO Reports
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
Si Lin Koo, Who Whong Wang, Han Chong Toh
In recent years, the impressive number of cancer immunotherapy drugs approved has been unprecedented-building on over a century of understanding on how the immune system combats cancer, and how cancer evades it. Leading the charge are the immune checkpoint inhibitor monoclonal antibodies, and adoptive cell therapy with chimeric- antigen-receptor (CAR)-T cell therapy. These breakthrough therapies have led to improved survival in patients with many advanced cancers. Some of the clinical outcomes have been striking, and may even be potentially curative in some terminal cancer patients...
September 2018: Annals of the Academy of Medicine, Singapore
Wei Zhang, Kimberly R Jordan, Brian Schulte, Enkhtsetseg Purev
Background: Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating acute lymphoblastic leukemia and non-Hodgkin's lymphoma with high rate complete responses. However, the broad clinical application of CAR T-cell therapy has been challenging, largely due to the lack of widespread ability to produce and high cost of CAR T-cell products using traditional methods of production. Automated cell processing in a closed system has emerged as a potential method to increase the feasibility of producing CAR T cells locally at academic centers due to its minimal reliance on experienced labor, thereby making the process less expensive and more consistent than traditional methods of production...
2018: Drug Design, Development and Therapy
Federica Costa, Rituparna Das, Jithendra Kini Bailur, Kavita Dhodapkar, Madhav V Dhodapkar
Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. Blockade of such inhibitory immune receptors (termed as "immune checkpoints") including PD-1/PD-L1 has led to impressive tumor regressions in several cancers...
2018: Frontiers in Immunology
Yibo Yin, Alina C Boesteanu, Zev A Binder, Chong Xu, Reiss A Reid, Jesse L Rodriguez, Danielle R Cook, Radhika Thokala, Kristin Blouch, Bevin McGettigan-Croce, Logan Zhang, Christoph Konradt, Alexandria P Cogdill, M Kazim Panjwani, Shuguang Jiang, Denis Migliorini, Nadia Dahmane, Avery D Posey, Carl H June, Nicola J Mason, Zhiguo Lin, Donald M O'Rourke, Laura A Johnson
We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial ( NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion...
December 21, 2018: Molecular Therapy Oncolytics
Amanda Rosewell Shaw, Masataka Suzuki
Adoptive T-cell immunotherapies, including chimeric antigen receptor-modified T-cells (CAR-T cells), have revolutionized cancer treatment, especially for hematologic malignancies. Clinical success of CAR-T cell monotherapy in solid tumors however, has been only modest. Oncolytic viruses provide direct cancer cell lysis, stimulate systemic immune responses, and have the capacity to provide therapeutic transgenes. Oncolytic virotherapy has shown great promise in many preclinical solid tumor models and the first oncolytic virus has been approved by the FDA for the treatment of advanced melanoma...
2018: Frontiers in Immunology
Bianca Simon, Ugur Uslu
Chimeric antigen receptor (CAR)-T cells are one of the impressive recent success stories of anti-cancer immunotherapy. Especially in hematological malignancies this treatment strategy has shown promising results leading to the recent approval of two CAR-T cell constructs targeting CD19 in the United States and the European Union. After the huge success in hematological cancers, the next step will be the evaluation of its efficacy in different solid tumors, which is currently investigated in preclinical as well as clinical settings...
October 4, 2018: Experimental Dermatology
Qing Zhang, Jinjing Xu, Jiage Ding, Hongyan Liu, Huizhong Li, Hailong Li, Mengmeng Lu, Yangna Miao, Zhenzhen Wang, Qiang Fu, Junnian Zheng
Adoptive chimeric antigen receptor (CAR) T or NK cells offer new options for cancer treatment. Clinical results indicate that CAR‑modified T cell (CAR‑T) therapy has curative therapeutic efficacy for hematological malignancies. However, the efficacy of the therapy in most solid tumors, including advanced renal cell carcinoma (RCC), remains highly limited. New regimens, including combination of CAR‑T cells with chemical drugs, must be studied to enhance the therapeutic efficacy of CAR‑T or NK cells for solid tumors...
September 24, 2018: Oncology Reports
Zahra Mahmoudjafari, Kelly G Hawks, Angela A Hsieh, Dragos Plesca, Katie S Gatwood, Kathryn A Culos
Administration of immune effector cell (IEC) therapy is a complex endeavor requiring extensive coordination and communication of various health care and administrative teams. Chimeric antigen receptor (CAR) T cells are the most established IEC therapy available. As of July 2018, there are two commercial gene therapy products, tisagenlecleucel and axicabtagene ciloleucel, approved by the United States Food & Drug Administration (FDA). To gain insight into the infrastructure and practices across the country, the American Society of Bone Marrow Transplant (ASBMT) Pharmacy Special Interest Group (SIG) conducted an electronic survey on the current administrative, logistical, and toxicity management practices of CAR T cell therapy across the United States...
September 25, 2018: Biology of Blood and Marrow Transplantation
Hasan Mollanoori, Hojat Shahraki, Yazdan Rahmati, Shahram Teimourian
Clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease9 (CRISPR/Cas9) technology, an acquired immune system in bacteria and archaea, has provided a new tool for accurately genome editing. Using only a single nuclease protein in complex with 2 short RNA as a site-specific endonuclease made it a simple and flexible genome editing tool to target nearly any genomic locus. Due to recent developments in therapeutic engineered T cell and effective responses of CD19-directed chimeric antigen receptor T cells (CART19) in patients with B-cell leukemia and lymphoma, adoptive T cell immunotherapy, particularly CAR-T cell therapy became a rapidly growing field in cancer therapy and recently Kymriah and Yescarta (CD19-directed CAR-T cells) were approved by FDA...
September 24, 2018: Human Immunology
Jun Zhang, L Jeffrey Medeiros, Ken H Young
Remarkable progress has been made in the field of cancer immunotherapy in the past few years. Immunotherapy has become a standard treatment option for patients with various cancers, including melanoma, lymphoma, and carcinomas of the lungs, kidneys, bladder, and head and neck. Promising immunotherapy approaches, such as chimeric antigen receptor (CAR) T cell therapy and therapeutic blockade of immune checkpoints, in particular cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 pathway (PD-1/PD-L1), have boosted the development of new therapeutic regimens for patients with cancer...
2018: Frontiers in Oncology
Teresa Poggio, Justus Duyster, Anna L Illert
T cell non-Hodgkin lymphoma (T-NHL) is a rare and heterogeneous group of neoplasms of the lymphoid system. With the exception of a few relatively indolent entities, T-NHL is typically aggressive, treatment resistant, and associated with poor prognosis. Relatively few options with proven clinical benefit are available for patients with relapsed or refractory disease. Immunotherapy has emerged as a promising treatment for the management of patients with hematological malignancies. The identification of tumor antigens has provided a large number of potential targets...
September 18, 2018: Cancers
Paolo Strati, Shabnum Patel, Loretta Nastoupil, Michelle A Fanale, Catherine M Bollard, Adam Y Lin, Leo I Gordon
Immune-based treatment strategies, such as checkpoint inhibition and chimeric antigen receptor (CAR) T cells, have started a new frontier for treatment in non-Hodgkin lymphoma (NHL). Checkpoint inhibition has been most successful in Hodgkin lymphoma, where higher expression of PD-L1 is correlated with better overall response rate. Combinations of checkpoint inhibition with various chemotherapy or biologics are in clinical trials, with initially promising results and manageable safety profiles. CAR T-cell therapies that target CD19 are a promising and attractive therapy for B-cell NHLs, with a product approved by the US Food and Drug Administration in 2017...
May 23, 2018: American Society of Clinical Oncology Educational Book
Lien Lybaert, Karim Vermaelen, Bruno G De Geest, Lutz Nuhn
During the last decade anti-tumor immune-therapy has opened novel opportunities to efficiently combat cancer progression. The introduction of DC- and CAR T-cell based therapies as well as the successful application of antibody-based inhibitor of immune checkpoints (CTLA-4, PD1 and PDL1) have boosted the field and led to an overall benefit for many patients. In situ cancer vaccination is an attractive strategy to further improve the therapeutic outcome, especially towards a more personalized and individually tailored immune response against the patient's mutanome...
September 14, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Fatemeh Nouri Rouzbahani, Mohammad Shirkhoda, Feridon Memari, Hassan Dana, Ghanbar Mahmoodi Chalbatani, Habibollah Mahmoodzadeh, Nasim Samarghandi, Elahe Gharagozlou, Mohammad Hosein Mohammadi Hadloo, Ali Reza Maleki, Ehsan Sadeghian, ElhamZainali Nia, Nedazainali Nia, Farimah Hadjilooei, Omid Rezaeian, Saeed Meghdadi, SeyedRohollah Miri, Fatameh Jafari, Elham Rayzan, Vahid Marmari
Cancer is a major burden of disease worldwide with considerable impact on society. The tide of immunotherapy has finally changed after decades of disappointing results and has become a clinically validated treatment for many cancers. Immunotherapy takes many forms in cancer treatment, including the adoptive transfer of ex vivo activated T cells, oncolytic viruses, natural killer cells, cancer vaccines and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways...
2018: Pakistan Journal of Biological Sciences: PJBS
Lorena Perez-Amill, Berta Marzal, Alvaro Urbano-Ispizua, Manel Juan, Beatriz Martín-Antonio
Seven years ago a chronic lymphocytic leukemia patient was by first time successfully treated with chimeric antigen receptor (CAR)-modified T cells (CART cells) to target CD19 over-expressed in tumor cells. This was the beginning of the development for a new type of immunotherapy treatment in cancer patients. Since then, identification of novel antigens expressed in the tumor cell, and optimization of both CARs constructs and protocols of administration have opened up new avenues to be able to treat successfully other hematological malignancies...
September 6, 2018: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
J Harvey Turner
The medical speciality of theranostic nuclear oncology has taken three-quarters of a century to move the stern light cast retrospectively by single-centre clinical reports, to the forepeak in the bow of our theranostic craft, where prospective randomised controlled multicentre clinical trials now illuminate the way forward. This recent reorientation of nuclear medicine clinical research practice to align with that of standard medical and radiation oncology protocols, reflects the paradigm shift toward individualised molecular oncology and precision medicine...
September 4, 2018: British Journal of Radiology
Hongshu Sui, Ningxia Ma, Ying Wang, Hui Li, Xiaoming Liu, Yanping Su, Jiali Yang
Lung cancer remains a leading cause of cancer-related mortality worldwide with the poor prognosis. Encouragingly, immune checkpoint blockade targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has dramatically changed the landscape for treatments in patients with non-small-cell lung cancer (NSCLC). However, only a small proportion of NSCLC patients responded to monotherapy of anti-PD-1/PDL1 agents; together, the development of resistance to anti-PD-1/PD-L1 therapy that leads to failure of anti-PD-1/PD-L1 therapy has significantly limited a broad applicability of the findings in clinical practices...
2018: Journal of Immunology Research
Shih-Feng Cho, Kenneth C Anderson, Yu-Tzu Tai
The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use...
2018: Frontiers in Immunology
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