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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThe traditional cancer therapy triumvirate of chemotherapy, radiation, and surgery is today being augmented with vaccines, cytokines, antibodies, targeted small-molecule drugs, and cell-based therapies such as immunotherapy. The hope is that combination therapies involving immune-based approaches will greatly enhance long-term survival. This article provides an overview of genetically modified cancer therapy with T cells.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ESoft Tissue Cancers\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELeukemia\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology Genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ESoft Tissue Cancers\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELeukemia\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology Genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EThe traditional cancer therapy triumvirate of chemotherapy, radiation, and surgery is today being augmented with vaccines, cytokines, antibodies, targeted small-molecule drugs, and cell-based therapies such as immunotherapy. The hope is that combination therapies involving immune-based approaches will greatly enhance long-term survival.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ECarl June, MD, University of Pennsylvania, Philadelphia, Pennsylvania, USA, offered an overview of genetically modified cancer therapy with T cells.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003ECancer immunotherapy has its roots in the 1957 success of the first allogeneic bone marrow transplant and the hypothesis of immunosurveillance. Intervening research culminated most recently with the 2011 US Food and Drug Administration approval of ipilimumab for the treatment of unresectable or metastatic melanoma. More recent discoveries in the field include the benefits of inhibition of programmed cell death 1 (PD1) and programmed death-ligand 1 (PDL1) proteins in melanoma, non-small cell lung cancer, and renal-cell carcinoma; and the durable remissions produced in B-cell acute and chronic lymphoblastic leukemia using chimeric antigen receptor (CAR)-modified T cells.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EThe origin of T-cell immunosurveillance of tumors likely reaches far back in human evolution. From an evolutionary perspective, the immune system is better equipped for tumor tolerance than tumor elimination. Modern-day research seeks to build on our natural condition through synthetic biology by engineering T cells capable of tumor elimination. A number of synthetic-biology approaches under exploration to overcome tolerance of tumors include tumor-specific targeting by CAR-modified T cells and T cells with modified T-cell receptor (TCR) [Maus MV et al. \u003Cem\u003EBlood\u003C\/em\u003E. 2014].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003ETumor tolerance can be circumvented by engineering bi-specific T cells. This process involves either modification of the TCR domain or modification of T cells with an extracellular chimeric protein. The intent in both approaches is to target the T cells for a tumor type. The antibody-based CAR approach offers the advantages of \u201coff-the-shelf\u201d technology and independence from the major histocompatibility complex class.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EIn CAR technology, the chimeric construct that targets an antigen on the tumor cells (eg, CD19) is introduced into T cells, typically using a lentiviral vector. The resulting CART 19 cells that harbor the anti-CD19 CAR construct on their surface will bind specifically to the CD19 protein on tumor cells. The approach produces antigen-dependent killing of tumor cells [Milone MC et al. \u003Cem\u003EMol Ther\u003C\/em\u003E. 2009] with a T-cell population consisting of both effector (cytotoxic) and central memory T cells [Hollyman D et al. \u003Cem\u003EJ Immunother\u003C\/em\u003E. 2009]. Destruction of the tumor cells does not involve swelling [Kalos M et al. \u003Cem\u003ESci Transl Med.\u003C\/em\u003E 2011]. The engineered T cells kill tumors regardless of the tumor cells\u0027 response to chemotherapy. Thus, even chemotherapy-resistant tumor cells will be killed, as long as they express the target antigen on their surface.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003ECurrent data do not explicitly favor TCR over CAR or vice versa, Dr June noted. TCR requires only about 10 targets for functional performance, whereas CAR requires about 100 surface targets. The TCR requirement for major histocompatibility complex (MHC) 1 expression and human leukocyte antigen (HLA) matching on the tumor cell, however, can be an important drawback that can permit tumor cells to escape immune surveillance. Both approaches provide long-lasting persistence of antitumor activity. It is likely that both will find their way into routine use, with a particular approach based on specific case circumstances.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EClinical trials of CAR T cells began in 1991, with the intent of retargeting T cells to treat patients with HIV. With more than a decade of use in patients, there is no evidence of integration near oncogenes or tumor suppressor genes, and no serious adverse events from the engineered T cells [Scholler J et al. \u003Cem\u003ESci Transl Med.\u003C\/em\u003E 2012]. Data indicate the safety of CAR-modified T cells as a therapeutic platform.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EDuring the past 2 decades, refinements to the first-generation CAR T cells have improved the binding structure of the domain and the potency of the engineered T cells. Tumor tolerance is under the control of 4 types of CD4 T cells, all of which have different targets of activity (Th1, intracellular pathogens and cancer; Th2, extracellular pathogens; Th17, chronic inflammation and autoimmunity; and Treg, effector T cells). By tailoring the CAR design, the differentiation of Th1 and Th17 cell types can be programmed, which researchers feel will have implications for specific tumor destruction.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EOne recent therapeutic target for CAR T cells has been chronic lymphocytic leukemia (CLL). Individuals with fludarabine-refractory CLL have a median overall survival of only 10 months. A CAR designed to produce T cells expressing CD19 has been tested in a clinical trial of CLL patients [Grupp S et al. \u003Cem\u003EN Engl J Med.\u003C\/em\u003E 2013]. To date, 3 late-stage CLL patients have responded to therapy, with reductions in cancer-cell numbers following CAR T-cell infusion.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EDr June and colleagues have also assessed the therapeutic value of CAR T cells in the treatment of pediatric and adult acute lymphoblastic leukemia (ALL). The team undertook a phase 1 trial [Maude SL et al. \u003Cem\u003EN Engl J Med.\u003C\/em\u003E 2014] involving 30 patients (25 pediatric patients) with ALL, and they achieved a complete response in 90% of patients, with partial or no response in the remaining 10%, and a 6-month overall survival of 78% (95% CI, 64% to 95%).\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EThe benefits of CD19 CAR T cells are accompanied by toxicities that include B-cell aplasia, tumor lysis syndrome, cytokine release syndrome, and macrophage activation syndrome. Nonetheless, these unprecedented survival results suggest that allogeneic transplantation for the treatment of ALL may eventually be replaced by CD19 CAR T-cell therapy.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003ESuch compelling benefits have spurred developmental efforts toward leukemia and lymphoma targets, as well as other cancers, including glioblastoma, prostate cancer, pancreatic cancer, and lung cancer, at a variety of institutions worldwide.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/36\/7\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022The editors would like to thank the many members of the 2014 Congress of the European Society for Medical Oncology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-921125541\u0022 data-figure-caption=\u0022The editors would like to thank the many members of the 2014 Congress of the European Society for Medical Oncology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure1\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/36\/7\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/36\/7\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/36\/7\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12108\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\n            \u003Cp id=\u0022p-15\u0022 class=\u0022first-child\u0022\u003EThe editors would like to thank the many members of the 2014 Congress of the European Society for Medical Oncology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/36\/7.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzops2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzops2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}