Advances in cell and gene therapy最新文献

{"title":"CAR T cells targeting αvβ3 integrin are effective against advanced cancer in preclinical models","authors":"Lars Wallstabe,&nbsp;Andreas Mades,&nbsp;Silke Frenz,&nbsp;Hermann Einsele,&nbsp;Christoph Rader,&nbsp;Michael Hudecek","doi":"10.1002/acg2.11","DOIUrl":"https://doi.org/10.1002/acg2.11","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Integrins are heterodimeric receptors that convey cell-to-cell and cell-to-matrix interactions. Integrin α_vβ₃ is expressed in several tumor entities including melanoma, glioblastoma, breast, pancreatic, and prostate cancer, where it promotes tumor cell survival and metastasis. Here, we generated α_vβ₃-specific chimeric antigen receptor (CAR) T cells and analyzed their antitumor function in preclinical models in vitro and in vivo. α_vβ₃-CARs comprising a super-humanized hLM609 targeting domain with either high or low affinity (hLM609v7, <i>K</i>_d = 3 nM vs hLM609v11, <i>K</i>_d = 160 nM) and equipped with either a long or a short IgG4-Fc extracellular spacer (229 vs 12 amino acids) were expressed in CD8⁺ and CD4⁺ T cells through lentiviral transduction. α_vβ₃-CAR T cells eliminated α_vβ₃-positive tumor cells rapidly and specifically, produced IFN-γ and IL-2 (CD4⁺ &gt; CD8⁺) and exhibited productive proliferation. In vitro, we observed the strongest reactivity with the higher affinity hLM609v7 α_vβ₃-CAR in the short spacer configuration, consistent with the tumor membrane-distal localization of the hLM609 epitope. In a murine xenograft model of metastatic A-375 melanoma, the strongest antitumor effect was mediated by the lower affinity hLM609v11 α_vβ₃-CAR. Notably, a single administration of hLM609v11 α_vβ₃-CAR T cells was able to induce complete elimination of melanoma lesions, leading to long-term tumor-free survival. These data establish α_vβ₃ integrin as a novel target for CAR T-cell immunotherapy and affirm our previous notion that binding domain affinity and spacer length can be calibrated to augment CAR reactivity. α_vβ₃-CAR T cells have therapeutic potential in several prevalent solid tumors, including melanoma and triple-negative breast cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71957750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR/Cas9 system: A promising technology for the treatment of inherited and neoplastic hematological diseases","authors":"Justin S. Antony,&nbsp;A.K.M. Ashiqul Haque,&nbsp;Andrés Lamsfus-Calle,&nbsp;Alberto Daniel-Moreno,&nbsp;Markus Mezger,&nbsp;Michael S.D. Kormann","doi":"10.1002/acg2.10","DOIUrl":"10.1002/acg2.10","url":null,"abstract":"<p>The ongoing advent of genome editing with programmable nucleases, including zinc-finger nuclease (ZFN), TAL effector nuclease (TALEN), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated RNA-guided endonuclease Cas9 (CRISPR/Cas9), have spurred the hematopoietic stem cell gene therapy (HSC-GT). In particular, CRISPR/Cas9-mediated gene editing revealed promising outcomes in several preclinical disease models including inherited and neoplastic hematological diseases. In this review, we focused on the utilization of the CRISPR/Cas9 system as a possible treatment option for hemoglobinopathies and hematological tumors. We summarize the recent advances with CRISPR/Cas9 and its therapeutic potential for genome editing in cells from hematopoietic origin. We also critically discussed the limitations inherent to the CRISPR/Cas9 and possible alternatives for the improvement of genome editing.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.10","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44568456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inaugural Editorial: A Welcome from the Co Editors-in-Chief, Dr. Syed A. Abutalib and Prof. Dr. Rupert Handgretinger","authors":"","doi":"10.1002/acg2.9","DOIUrl":"10.1002/acg2.9","url":null,"abstract":"","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45973982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A brief history of bone marrow transplantation","authors":"Shaun McCann,&nbsp;Robert Peter Gale","doi":"10.1002/acg2.8","DOIUrl":"10.1002/acg2.8","url":null,"abstract":"Bone marrow has been a source of nutrition for many centuries. Although xenotransplants were described in an ancient Irish manuscript, it was not until adverse hematological effects of ionizing radiation were known during World War II that the stimulus for bone marrow transplantation was established. International cooperation and the determination of many scientists/physicians have resulted in the widespread use of transplants to treat leukemias and other hematological and immune disorders. Newer forms of immune modulation are being studied but are unlikely to replace hematopoietic cell transplants.","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48716415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre- and posttransplant use of mogamulizumab in patients with aggressive adult T-cell leukemia-lymphoma: A statement from key opinion leaders in Japan","authors":"Shigeo Fuji,&nbsp;Koji Kato,&nbsp;Nobuaki Nakano,&nbsp;Takashi Ishida,&nbsp;Kenji Ishitsuka,&nbsp;Ilseung Choi,&nbsp;Ken-ichi Matsuoka,&nbsp;Atae Utsunomiya","doi":"10.1002/acg2.5","DOIUrl":"10.1002/acg2.5","url":null,"abstract":"<p>Recently, the anti-CCR4 antibody mogamulizumab (Moga, Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan) was approved as a treatment for CCR4-positive adult T-cell leukemia-lymphoma (ATL) in Japan. We use Moga before or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with aggressive ATL. A recent retrospective analysis using a database from a nationwide survey showed that the use of Moga before allo-HSCT was associated with an increased risk of severe/steroid-refractory acute GVHD and inferior overall survival. Meanwhile, it was reported that a number of patients with chemotherapy-refractory ATL achieved disease control with Moga, including those who subsequently underwent allo-HSCT. To address these issues pertaining to Moga in transplant-eligible patients with ATL, a key opinion leader (KOL) meeting comprising hematologists and transplant physicians was conducted by Kyowa Hakko Kirin Co., Ltd. in Japan. The goal of this KOL meeting was to design a framework to guide decision-making on the use of Moga in transplant-eligible patients with ATL. KOLs first presented their experiences, and after a subsequent discussion, the KOLs agreed on the key scientific statement as summarized in this Expert Commentary. Our experiences suggest that a good number of patients benefited from Moga, achieving disease control that was often unattainable by conventional chemotherapies. However, as our statement is based largely on retrospective studies and real clinical practice, it requires further validation. Nevertheless, we believe that this statement should help efficiently guide decision-making concerning Moga use in transplant-eligible patients with ATL.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44973578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRUCKs with IL-18 payload: Toward shaping the immune landscape for a more efficacious CAR T-cell therapy of solid cancer","authors":"Markus Chmielewski,&nbsp;Hinrich Abken","doi":"10.1002/acg2.7","DOIUrl":"10.1002/acg2.7","url":null,"abstract":"<p>Adoptive therapy with chimeric antigen receptor (CAR)-modified T cells achieved remissions of so far refractory leukemia/lymphoma; however, the treatment of solid tumors still remains challenging. This is thought to be due to the hostile conditions of the tumor stroma and the repressive immune cell infiltrate. Most recently, CAR T cells are being used as redirected “living factories” to deposit immune-modulating cytokines in the tumor tissue aiming at converting the immune cell environment into a more favorite one to sustain a productive antitumor response. IL-18 releasing CAR- or T cell receptor (TCR)-modified T cells showed superior antitumor activities in several tumor models. Such IL-18 TRUCKs or “4th generation” CAR T cells are going to change our concepts of treating tumors and delivering drugs to predefined lesions in the near future.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46938988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hematopoietic stem cell transplantation for T-cell lymphoma","authors":"Takafumi Shichijo,&nbsp;Shigeo Fuji","doi":"10.1002/acg2.6","DOIUrl":"10.1002/acg2.6","url":null,"abstract":"<p>As peripheral T-cell lymphomas (PTCL) are rare and heterogeneous groups of non-Hodgkin lymphomas, it is practically difficult to conduct randomized controlled trials to establish standard treatment strategies. There is still no consensus regarding the optimal treatment strategy for patients with PTCL. Moreover, the survival outcomes of PTCL, excluding anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma, remain disappointing although novel agents have become available recent years. The aim of this review is to summarize the information regarding hematopoietic stem cell transplantation (HSCT) for PTCL including both autologous (auto-) and allogeneic (allo-) HSCT. In the first-line setting, up-front auto-HSCT is generally recommended for patients with PTCL, especially with complete remission 1 (CR1). On the other hand, up-front allo-HSCT might be recommended for patients with high-risk PTCL, although the study incorporating up-front allo-HSCT is limited. In the salvage setting, auto-HSCT might be considered in patients with chemosensitive disease, especially with CR. Allo-HSCT might also be considered, although the data of allo-HSCT in the salvage setting is still limited. Further investigation to optimize the application of HSCT in patients with PTCL is warranted in the future.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46519429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}