Genetically engineered T cells to target EGFRvIII expressing glioblastoma

Bullain, Szófia S.; Sahin, Ayguen; Szentirmai, Oszkar; Sanchez, Carlos E.; Lin, Ning; Baratta, Elizabeth; Waterman, Peter; Weissleder, Ralph; Mulligan, Richard C.; Carter, Bob S.

doi:10.1007/s11060-009-9889-1

Cited by 63 publications

(51 citation statements)

References 27 publications

(31 reference statements)

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“…Bullian and colleagues created an EGFRvIII-specific CAR, MR1-f, and demonstrated that human T cells genetically modified with MR1-f specifically recognized EGFRvIII-expressing tumor cell lines and delayed tumor growth in vivo in mouse models (Bullain et al, 2009). Similarly, Ohno and colleagues engineered T cells expressing a CAR against EGFRvIII based on a mouse mAb, 3C10; they demonstrated in vivo inhibition of intracranial tumor growth in mice (Ohno et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Recognition of Glioma Stem Cells by Genetically Modified T Cells Targeting EGFRvIII and Development of Adoptive Cell Therapy for Glioma

Morgan

Johnson²,

Davis³

et al. 2012

Human Gene Therapy

264

207

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No curative treatment exists for glioblastoma, with median survival times of less than 2 years from diagnosis. As an approach to develop immune-based therapies for glioblastoma, we sought to target antigens expressed in glioma stem cells (GSCs). GSCs have multiple properties that make them significantly more representative of glioma tumors than established glioma cell lines. Epidermal growth factor receptor variant III (EGFRvIII) is the result of a novel tumor-specific gene rearrangement that produces a unique protein expressed in approximately 30% of gliomas, and is an ideal target for immunotherapy. Using PCR primers spanning the EGFRvIII-specific deletion, we found that this tumor-specific gene is expressed in three of three GCS lines. Based on the sequence information of seven EGFRvIII-specific monoclonal antibodies (mAbs), we assembled chimeric antigen receptors (CARs) and evaluated the ability of CAR-engineered T cells to recognize EGFRvIII. Three of these anti-EGFRvIII CAR-engineered T cells produced the effector cytokine, interferon-c, and lysed antigen-expressing target cells. We concentrated development on a CAR produced from human mAb 139, which specifically recognized GSC lines and glioma cell lines expressing mutant EGFRvIII, but not wild-type EGFR and did not recognize any normal human cell tested. Using the 139-based CAR, T cells from glioblastoma patients could be genetically engineered to recognize EGFRvIII-expressing tumors and could be expanded ex vivo to large numbers, and maintained their antitumor activity. Based on these observations, a c-retroviral vector expressing this EGFRvIII CAR was produced for clinical application.

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Section: Discussionmentioning

confidence: 99%

Recognition of Glioma Stem Cells by Genetically Modified T Cells Targeting EGFRvIII and Development of Adoptive Cell Therapy for Glioma

Morgan

Johnson²,

Davis³

et al. 2012

Human Gene Therapy

264

207

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show abstract

“…When expressed on T cells, the receptor bypasses the need for antigen presentation on HLA since the scFv binds directly to cell surface antigens. Recent studies focused on the development of scFv receptor constructs that incorporate the CD28 costimulatory domain linked with the TCRZ signaling domain [360], have shown increased antitumor function in vitro and in experimental murine models of colon carcinoma and GBM [361,362] [363]. A phase I/II study to evaluate the safety and biological activity of escalating doses of autologous CMV-specific cytotoxic T-lymphocytes (CTL) genetically modified to express chimeric TCR specific for the HER2 molecule is planned in patients with HER2-positive GBM (NCT01109095).…”

Section: Genetically Engineered T Cellsmentioning

confidence: 99%

New Perspectives in Glioma Immunotherapy

Daga¹,

Bottino²,

Castriconi³

et al. 2011

CPD

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Glioblastoma (GBM) is a deadly tumor, which in spite of surgery and radio/chemotherapy frequently undergoes relapses related to the infiltration of the normal parenchyma and to resistance to cytotoxic and radiation therapy. Immunotherapy may represent a promising approach, which may complement existing therapies with the aim of eliminating residual tumor cells, through their selective targeting by immune effector cells or antibodies. This goal can be achieved through different approaches, based either on the induction of an immune response of the host, or by the injection of in vitro generated effector cells or monoclonal antibodies. Recent advances in the immunobiology of GBM and of its stem cell compartment will help in the development of more effective immunotherapy protocols. To this aim, the identification of antigens and receptors involved in GBM/immune cell interactions and of GBM immune escape mechanisms will provide new targets and tools. In this review we will discuss active immunotherapy approaches, including molecular-defined, GBM cell-based and dendritic-cell based vaccines. In addition, cytokines such as interferons and several interleukins can be used to enhance the immune response, both as recombinant molecules and by gene transfer technologies. Monoclonal antibodies or other ligands specific for GBM- or neovasculature-associated targets are now available in different genetically modified formats and can be used as such or for the targeted delivery of active compounds. Finally the in vitro activation and expansion of specific or innate immunity effector cells endowed with anti-GBM properties may provide an additional weapon for adoptive imunotherapy approaches.

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“…Recent studies have shown an expansion of receptors against other antigen targets on solid tumors, such as epidermal growth factor receptor vIII on glioblastoma [116], prostate stem cell antigen on prostate cancer [117], fetal acetylcholine receptor on rhabdomyosarcoma [118], and MUC1 on breast cancer cells [17]. In addition, novel, antigenic targets on hematological cancers have been addressed, such as CD38 on non-Hodgkin's lymphoma [119].…”

Section: Discussionmentioning

confidence: 99%

Genetic redirection of T cells for cancer therapy

Westwood

Kershaw

2010

Journal of Leukocyte Biology

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Adoptive immunotherapy can induce dramatic tumor regressions in patients with melanoma or viral-induced malignancies, but extending this approach to many common cancers has been hampered by a lack of naturally occurring tumor-specific T cells. In this review, we describe recent advances in the genetic modification of T cells using genes encoding cell-surface receptors specific for tumor-associated antigen. Using genetic modification, the many functional properties of T cells, including cytokine secretion and cytolytic capacity, are redirected from their endogenous specificity toward the elimination of tumor cells. Advances in gene design, vectors, and cell production are discussed, and details of the progress in clinical application of this approach are provided.

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Genetically engineered T cells to target EGFRvIII expressing glioblastoma

Cited by 63 publications

References 27 publications

Recognition of Glioma Stem Cells by Genetically Modified T Cells Targeting EGFRvIII and Development of Adoptive Cell Therapy for Glioma

Recognition of Glioma Stem Cells by Genetically Modified T Cells Targeting EGFRvIII and Development of Adoptive Cell Therapy for Glioma

New Perspectives in Glioma Immunotherapy

Genetic redirection of T cells for cancer therapy

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