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Chimeric antigen therapy

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https://www.readbyqxmd.com/read/28223167/intracavitary-t4-immunotherapy-of-malignant-mesothelioma-using-pan-erbb-re-targeted-car-t-cells
#1
Astero Klampatsa, Daniela Y Achkova, David M Davies, Ana C Parente-Pereira, Natalie Woodman, James Rosekilly, Georgina Osborne, Thivyan Thayaparan, Andrea Bille, Michael Sheaf, James F Spicer, Juliet King, John Maher
Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy...
February 18, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28222796/new-development-in-car-t-cell-therapy
#2
REVIEW
Zhenguang Wang, Zhiqiang Wu, Yang Liu, Weidong Han
Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have yielded unprecedented efficacy in B cell malignancies, most remarkably in anti-CD19 CAR-T cells for B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate. However, tumor antigen escape has emerged as a main challenge for the long-term disease control of this promising immunotherapy in B cell malignancies. In addition, this success has encountered significant hurdles in translation to solid tumors, and the safety of the on-target/off-tumor recognition of normal tissues is one of the main reasons...
February 21, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28215040/who-should-receive-a-transplant-for-acute-lymphoblastic-leukaemia
#3
REVIEW
Rishi Dhawan, David I Marks
Allogeneic haematopoietic cell transplantation continues to be an important curative therapy for acute lymphoblastic leukaemia (ALL). Traditionally accepted indications for allografting adult ALL patients need reevaluation in light of outcomes with paediatric-like intensive regimens. Minimal residual disease status and oncogenetics can be used for restratification of standard risk patients. A greater body of data on haematopoietic cell transplantation (HCT) outcomes from haploidentical and cord blood donor sources has been generated in recent years...
February 18, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28210259/resolution-of-cancer-promoting-inflammation-a-new-approach-for-anticancer-therapy
#4
REVIEW
Qi Zhang, Bo Zhu, Yongsheng Li
Inflammation is a protective response that eliminates harmful stimuli and restores tissue homeostasis, whereas the failure to resolve inflammation leads to the development of malignancies. Immune cells in the tumor inflammatory microenvironment endow cancer cells with their specific hallmarks, including mutations, metabolic reprograming, angiogenesis, invasion, and metastasis. Targeting the inflammatory microenvironment with anti-inflammatory drugs (e.g., aspirin) or by enhancing antitumor immunity (e.g., chimeric antigen receptor T cell therapy) has been extensively investigated and has achieved promising results in many cancers...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28205134/minimal-residual-disease-in-acute-lymphoblastic-leukemia-how-to-recognize-and-treat-it
#5
REVIEW
Nicholas J Short, Elias Jabbour
In recent years, the identification of minimal residual disease (MRD) that persists after chemotherapy has emerged as the most powerful tool in determining the prognosis of patients with ALL, often superseding historically relevant prognostic factors. Multiple methods to detect MRD exist, each with their own advantages and disadvantages. Multiparameter flow cytometry and quantitative polymerase chain reaction are the most commonly used methods of MRD detection in clinical practice, although there is promise in the use of more sensitive assays utilizing next-generation sequencing that may be able to further refine MRD-based risk stratification...
January 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28202953/fully-human-cd19-specific-chimeric-antigen-receptors-for-t-cell-therapy
#6
D Sommermeyer, T Hill, S M Shamah, A I Salter, Y Chen, K M Mohler, S R Riddell
Impressive results have been achieved by adoptively transferring T-cells expressing CD19-specific CARs with binding domains from murine mAbs to treat B-cell malignancies. T-cell mediated immune responses specific for peptides from the murine scFv antigen-binding domain of the CAR can develop in patients and result in premature elimination of CAR-T-cells increasing the risk of tumor relapse. As fully human scFv might reduce immunogenicity, we generated CD19-specific human scFvs with similar binding characteristics as the murine FMC63-derived scFv using human Ab/DNA-libraries...
February 16, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28199983/a-versatile-system-for-rapid-multiplex-genome-edited-car-t-cell-generation
#7
Jiangtao Ren, Xuhua Zhang, Xiaojun Liu, Chongyun Fang, Shuguang Jiang, Carl H June, Yangbing Zhao
The therapeutic potential of CRISPR system has already been demonstrated in many instances and begun to overlap with the rapidly expanding field of cancer immunotherapy, especially on the production of genetically modified T cell receptor or chimeric antigen receptor (CAR) T cells. Efficient genomic disruption of multiple gene loci to generate universal donor cells, as well as potent effector T cells resistant to multiple inhibitory pathways such as PD-1 and CTLA4 is an attractive strategy for cell therapy...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28197367/targeting-ewing-sarcoma-with-activated-and-gd2-specific-chimeric-antigen-receptor-engineered-human-nk-cells-induces-upregulation-of-immune-inhibitory-hla-g
#8
Sareetha Kailayangiri, Bianca Altvater, Christian Spurny, Silke Jamitzky, Sonja Schelhaas, Andreas H Jacobs, Constanze Wiek, Katharina Roellecke, Helmut Hanenberg, Wolfgang Hartmann, Heinz Wiendl, Susann Pankratz, Jutta Meltzer, Nicole Farwick, Lea Greune, Maike Fluegge, Claudia Rossig
Activated and in vitro expanded natural killer (NK) cells have substantial cytotoxicity against many tumor cells, but their in vivo efficacy to eliminate solid cancers is limited. Here, we used chimeric antigen receptors (CARs) to enhance the activity of NK cells against Ewing sarcomas (EwS) in a tumor antigen-specific manner. Expression of CARs directed against the ganglioside antigen GD2 in activated NK cells increased their responses to GD2+ allogeneic EwS cells in vitro and overcame resistance of individual cell lines to NK cell lysis...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28196594/inactivation-of-interferon-receptor-promotes-the-establishment-of-immune-privileged-tumor-microenvironment
#9
Kanstantsin V Katlinski, Jun Gui, Yuliya V Katlinskaya, Angelíca Ortiz, Riddhita Chakraborty, Sabyasachi Bhattacharya, Christopher J Carbone, Daniel P Beiting, Melanie A Girondo, Amy R Peck, Ellen Puré, Priya Chatterji, Anil K Rustgi, J Alan Diehl, Constantinos Koumenis, Hallgeir Rui, Serge Y Fuchs
Refractoriness of solid tumors, including colorectal cancers (CRCs), to immunotherapies is attributed to the immunosuppressive tumor microenvironment that protects malignant cells from cytotoxic T lymphocytes (CTLs). We found that downregulation of the type I interferon receptor chain IFNAR1 occurs in human CRC and mouse models of CRC. Downregulation of IFNAR1 in tumor stroma stimulated CRC development and growth, played a key role in formation of the immune-privileged niche, and predicted poor prognosis in human CRC patients...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28186088/current-status-of-immunotherapy-for-gastrointestinal-stromal-tumor
#10
REVIEW
Y Tan, J C Trent, B A Wilky, D A Kerr, A E Rosenberg
Gastrointestinal stromal tumors (GIST) contain tumor-infiltrating immune cells and their presence provides an opportunity and rationale for developing effective forms of immunotherapy. The types of tumor-infiltrating inflammatory cells and relevant immune checkpoint inhibitors are the focus of active investigation. The most numerous tumor-infiltrating inflammatory cells are tumor-associated macrophages (TAMs) and CD3+ T cells. Studies have shown that patients with GISTs that harbor increased numbers of CD3+ T cells have better outcomes...
February 10, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28184969/augmented-anti-tumor-activity-of-nk-92-cells-expressing-chimeric-receptors-of-tgf-%C3%AE-r-ii-and-nkg2d
#11
Zhongjuan Wang, Linghua Guo, Yuan Song, Yinsheng Zhang, Dandan Lin, Bo Hu, Yu Mei, Dedy Sandikin, Haiyan Liu
The capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-β to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-β type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (TN chimeric receptor)...
February 9, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28169418/allogeneic-transplantation-using-cd34-selected-peripheral-blood-progenitor-cells-combined-with-non-mobilized-donor-t%C3%A2-cells-for-refractory-severe-aplastic-anaemia
#12
Enkhtsetseg Purev, Xin Tian, Georg Aue, Jeremy Pantin, Phuong Vo, Reem Shalabi, Robert N Reger, Lisa Cook, Catalina Ramos, Elena Cho, Tat'yana Worthy, Hanh Khuu, David Stroncek, Neal S Young, Richard W Childs
Allogeneic haematopoietic stem cell transplantation is curative for severe aplastic anaemia (SAA) unresponsive to immunosuppressive therapy. To reduce chronic graft-versus-host disease (GVHD), which occurs more frequently after peripheral blood stem cell (PBSC) transplantation compared to bone-marrow transplantation (BMT), and to prevent graft rejection, we developed a novel partial T-cell depleted transplant that infuses high numbers of granulocyte colony-stimulating factor-mobilized CD34(+) selected PBSCs combined with a BMT-equivalent dose of non-mobilized donor T-cells...
February 7, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28169004/immunotherapy-in-ovarian-cancer
#13
Venkatesh Krishnan, Jonathan S Berek, Oliver Dorigo
Immunotherapy aims to develop combination approaches that simultaneously augment immunity while preventing local immune suppression. Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for patients with ovarian cancer are inadequate. Advances in immunotherapy offer a promising frontier for treating ovarian tumors. Multiple immunotherapeutic modalities are currently developed and tested in clinical trials. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing...
November 15, 2016: Current Problems in Cancer
https://www.readbyqxmd.com/read/28154831/targeting-o-acetyl-gd2-ganglioside-for-cancer-immunotherapy
#14
REVIEW
Julien Fleurence, Sophie Fougeray, Meriem Bahri, Denis Cochonneau, Béatrice Clémenceau, François Paris, Andras Heczey, Stéphane Birklé
Target selection is a key feature in cancer immunotherapy, a promising field in cancer research. In this respect, gangliosides, a broad family of structurally related glycolipids, were suggested as potential targets for cancer immunotherapy based on their higher abundance in tumors when compared with the matched normal tissues. GD2 is the first ganglioside proven to be an effective target antigen for cancer immunotherapy with the regulatory approval of dinutuximab, a chimeric anti-GD2 therapeutic antibody. Although the therapeutic efficacy of anti-GD2 monoclonal antibodies is well documented, neuropathic pain may limit its application...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28153859/high-response-to-anti-cd19-car-therapy-in-dlbcl
#15
(no author information available yet)
According to an interim analysis of phase II data from a study of the anti-CD19 chimeric antigen receptor T-cell therapy KTE-C19, 76% of 51 patients with diffuse large B-cell lymphoma responded to the treatment; 47% had a complete response. After 3 months, 33% continued to experience a complete response.
February 2, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28151713/immune-therapies-in-multiple-myeloma
#16
EDITORIAL
Shaji K Kumar, Kenneth C Anderson
Treatment paradigms have changed rapidly for multiple myeloma, and immune therapies have taken center stage. Advances in therapies for myeloma have led to a dramatic improvement in the survival of patients with this incurable malignancy. The immune system is significantly impaired in patients with myeloma as a result of the disease leading to suppression of normal plasma cells as well the negative effects on cellular immunity. Given this scenario, immune approaches have not been successful until recently. Monoclonal antibodies directed against CD38 (daratumumab) and SLAMF7 (elotuzumab) are already in the clinic, and several other antibodies directed against different plasma cell antigens are under evaluation...
November 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28147367/mesenchymal-stromal-cell-therapy-in-crohn-s-disease
#17
Geoffrey M Forbes
BACKGROUND: Mesenchymal stromal cells (MSC) are multipotent adult stem cells with immunomodulatory properties. They uniquely express HLA class I antigen at a low level, and do not express HLA class II. Hence, for allogeneic administration, donor to recipient matching is not required; yet a prolonged chimeric state does not occur. Contrary to haematopoietic stem cell transplantation, cytotoxic drug therapy is not required to harvest, or administer, cells. Key Messages: MSC are obtained from marrow, adipose tissue or placenta...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28143740/engineering-hiv-resistant-anti-hiv-chimeric-antigen-receptor-t-cells
#18
Malika Hale, Taylor Mesojednik, Guillermo S Romano Ibarra, Jaya Sahni, Alison Bernard, Karen Sommer, Andrew M Scharenberg, David J Rawlings, Thor A Wagner
The treatment or cure of HIV infection by cell and gene therapy has been a goal for decades. Recent advances in both gene editing and chimeric antigen receptor (CAR) technology have created new therapeutic possibilities for a variety of diseases. Broadly neutralizing monoclonal antibodies (bNAbs) with specificity for the HIV envelope glycoprotein provide a promising means of targeting HIV-infected cells. Here we show that primary human T cells engineered to express anti-HIV CARs based on bNAbs (HIVCAR) show specific activation and killing of HIV-infected versus uninfected cells in the absence of HIV replication...
January 28, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28138559/transient-stimulation-expands-superior-antitumor-t-cells-for-adoptive-therapy
#19
Yuki Kagoya, Munehide Nakatsugawa, Toshiki Ochi, Yuchen Cen, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O Butler, Naoto Hirano
Adoptive cell therapy is a potentially curative therapeutic approach for patients with cancer. In this treatment modality, antitumor T cells are exponentially expanded in vitro prior to infusion. Importantly, the results of recent clinical trials suggest that the quality of expanded T cells critically affects their therapeutic efficacy. Although anti-CD3 mAb-based stimulation is widely used to expand T cells in vitro, a protocol to generate T cell grafts for optimal adoptive therapy has yet to be established...
January 26, 2017: JCI Insight
https://www.readbyqxmd.com/read/28129122/phase-1-results-of-zuma-1-a-multicenter-study-of-kte-c19-anti-cd19-car-t-cell-therapy-in-refractory-aggressive-lymphoma
#20
Frederick L Locke, Sattva S Neelapu, Nancy L Bartlett, Tanya Siddiqi, Julio C Chavez, Chitra M Hosing, Armin Ghobadi, Lihua E Budde, Adrian Bot, John M Rossi, Yizhou Jiang, Allen X Xue, Meg Elias, Jeff Aycock, Jeff Wiezorek, William Y Go
Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m(2)) and fludarabine (30 mg/m(2)) for 3 days followed by KTE-C19 at a target dose of 2 × 10(6) CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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