A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR

Torikai, Hiroki; Reik, Andreas; Liu, Pei Qi; Zhou, Yuanyue; Zhang, Ling; Maiti, Sourindra N.; Huls, Helen; Miller, Jeffrey C.; Kebriaei, Partow; Rabinovitch, Brian; Lee, Dean A.; Champlin, Richard E.; Bonini, Chiara; Naldini, Luigi; Rebar, Edward J.; Gregory, Philip D.; Holmes, Michael C.; Cooper, Laurence J.N.

doi:10.1182/blood-2012-01-405365

Cited by 458 publications

(374 citation statements)

References 50 publications

(55 reference statements)

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“…The SB system we employed here is frequently used for gene delivery and longterm transgene expression due to its lower cost and better safety profile (30)(31)(32). We used the SB system to transfer HERV-K-CAR into PBMCs from BC patients and normal female donors to propagate K-CAR T cells, and showed that these cells display CAR-dependent effector function and anti-proliferative effects.…”

Section: The Profiles Of Gene Expression In Tumor Biopsiesmentioning

confidence: 99%

Innovative Strategies for Breast Cancer Immunotherapy

Wang-Johanning¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information ABSTRACTAntitumor effects of human endogenous retrovirus type K (HERV-K) specific short hairpin RNAs (shRNAs) were determined in vitro and in vivo. We observed expression of HERV-K in breast cancer (BC) and inhibition of BC cell proliferation and induction of apoptosis in BC cells treated with anti-HERV-K antibodies. Furthermore, significantly slower growth was observed in BC cells transfected with a shRNA targeting the HERV-K env mRNA (shRNAenv) compared with a shRNA targeting a scrambled RNA sequence (shRNAc). Significantly reduced numbers of colonies formed in soft agar when HERV-K env was knocked down in BC cell lines, compared to treatment with shRNAc, and significantly reduced tumor sizes and weights were demonstrated in mice xenografted with MDA-MB-231, MDA-MB-435.eb1, and SKBR3 BC cells stably transfected with shRNAenv, compared to cells stably transfected with a shRNAc. Downregulation of HERV-K with its targeting shRNA caused an increase of BC cells in the S phase and a corresponding decrease of cells in the G1 or G2-M. HERV-K viral RNAs were found to be involved in BC tumorigenesis via effects on not only p53 signaling pathways, but also other major signaling pathways that play critically important roles in tumorigenesis. SUBJECT TERMS

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Section: The Profiles Of Gene Expression In Tumor Biopsiesmentioning

confidence: 99%

Innovative Strategies for Breast Cancer Immunotherapy

Wang-Johanning¹

2014

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“…The fundamental idea of an "off-the-shelf" CAR T cell is a genetically edited CAR T cell with deleted endogenous αβ TCR and HLA molecules which can be achieved by the zinc finger nuclease technology [64]. Such CAR T cells are expected to be applied to a number of patients without causing graft-versus-host disease (GvHD) and without being eliminated by the host immune cells while providing CAR-mediated effector functions against cancer cells.…”

Section: Universal Car T Cellsmentioning

confidence: 99%

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

Holzinger¹,

Abken²

2017

Immunotherapy - Myths, Reality, Ideas, Future

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Adoptive therapy of malignant diseases by chimeric antigen receptor (CAR) redirected T cells takes advantage of the patient's own immune system to recognize and destroy cancer cells. This is impressively demonstrated by the induction of complete and lasting remissions of leukemia with CAR-engineered T cells in early phase trials. Recent developments in optimizing the CAR design, in the recognition of target cells and the production of modified cells for clinical use, have paved the path for a broader application than currently explored. The chapter reviews the differences in CAR design, the success in the treatment of hematologic malignancies, the challenges in treating solid cancer, the treatment-related toxicities, and strategies to improve safety of CAR T cell therapy. Challenges for future applications are discussed.

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“…The ability to use banked CAR T-cells, generated from non-HLA matched donors in an 'off-the-shelf' manner has been an attractive prospect that has driven attempts to overcome HLA-barriers, both in terms of allo-reactivity from infused cells and host-mediated rejection [6][7][8]. T-cells encode highly specific heterodimeric αβ T-cell receptors, and these are the key mediators of major histocompatibility complex (MHC) recognition leading to GVHD.…”

mentioning

confidence: 99%

“…T-cells encode highly specific heterodimeric αβ T-cell receptors, and these are the key mediators of major histocompatibility complex (MHC) recognition leading to GVHD. Strategies to disrupt T-cell receptor (TCR) expression have used a variety of reagents including RNA interference (RNAi) [9] and targeted gene disruption using directed DNA nucleases such as Zinc Finger Nucleases [6,7], Meganucleases [10], MegaTALs [11,12], and Transcription activator like effector nucleases (TALENs) [8,13,14]. The latter operate at the genomic level, directing engineered endonucleases to highly specific loci to create double stranded DNA cleavage.…”

mentioning

confidence: 99%