A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells

Wang, Xiuli; Chang, Wen Chung; Wong, ChingLam W.; Colcher, David; Sherman, Mark A.; Ostberg, Julie R.; Forman, Stephen J.; Riddell, Stanley R.; Jensen, Michael C.

doi:10.1182/blood-2011-02-337360

Cited by 518 publications

(527 citation statements)

References 35 publications

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“…The CD19R:CD28:z/EGFRt -epHIV7 contains: (1) the CAR sequence consisting of the V H and V L gene segments of the CD19-specific FMC63 mAb, an IgG4 hinge-CH2CH3, the transmembrane, and cytoplasmic domains of the costimulatory molecule CD28, and the cytoplasmic domain of the CD3z chain 44 ; (2) the ribosomal skip T2A sequence and (3) the truncated human EGFR (EGFRt) sequence as previous described. 30 In some cases, the CD19R:CD28:z/EGFRt with mutations at two sites (L235E; N297Q) within the CH2 region on the IgG4-Fc spacers (CD19R(EQ)) was used ( Fig. S8A and S8B).…”

Section: Dna Constructsmentioning

confidence: 99%

“…Ten days after the lentiviral transduction, the truncated human EGFR C (EGFRt C ) T cells were then enriched 30 and further expanded by REM in the presence of 50U/mL rhIL-2 and 0.5ng/mL rhIL-15 (CellGenix).…”

Section: Freshly Isolated Cd8mentioning

confidence: 99%

“…30 EGFRt C CD19-CAR T cells were immunomagnetically enriched to 90% purity and underwent 3 cycles of REM stimulation and expansion. Studies were then performed using the CD19CAR CTLs derived from CD8 C T N/SCM (T N/SCM -CD19R) and CD8 C T CM (T CM -CD19R) (Fig.…”

Section: Cd19car Ctls Derived From Cd8mentioning

confidence: 99%

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Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

et al. 2015

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CD62LC precursors enriched for na€ ıve and stem cell memory precursors (T N/SCM ) with that of T CM . We found that cytotoxic T cells (CTLs) derived from T CM transcribed higher levels of CD28, FOS, INFg, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of g-chain cytokines compared to CTLs derived from T N/SCM . Higher frequencies of CTLs derived from T CM retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/Scid IL-2RgC null mice, CD8 C T CM derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8C T CM derived CD19CAR C CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8 C T N/SCM derived counterparts. These studies support the use of T CM enriched cell products for adoptive therapy of cancer.

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Section: Dna Constructsmentioning

confidence: 99%

Section: Freshly Isolated Cd8mentioning

confidence: 99%

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Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

et al. 2015

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“…Another strategy takes an advantage of marking CAR T cells with a unique cell surface molecule to which an approved therapeutic antibody binds. For instance, the truncated EGFR, co-expressed with the CAR by the same T cell, can be targeted by the antibody cetuximab which efficiently eliminates those marked cells [117]. Efforts are also being undertaken to coexpress the targetable epitope within the extracellular part of the CAR, thereby making the CAR itself a target of a depleting antibody [118].…”

Section: (V) Car T Cell Eliminationmentioning

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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“…An alternative strategy that is in development involves engineering of CAR-modified T cells with a truncated human epidermal growth factor (EGF) receptor (EGFR) that lacks the EGF-binding domain and the intracellular signaling domain, but retains the extracellular epitope to which the clinically available anti-EGFR monoclonal antibody, cetuximab (Erbitux), binds, potentially allowing the use of systemic administration of cetuximab as a strategy to deplete engineered EGFR ? T cells [65].…”

Section: Strategies To Improve the Safety Of Car-modified T Cellsmentioning

confidence: 99%

Chimeric antigen receptor modified T cell therapy for B cell malignancies

Turtle

2013

Int J Hematol

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Adoptive transfer of tumor-reactive T cells into cancer patients with the intent of inducing a cytotoxic antitumor effector response and durable immunity has long been proposed as a novel therapy for a broad range of malignancies; however, local and systemic tolerance mechanisms have hindered the generation of effective T cell therapies and limited the clinical efficacy of this approach in cancer patients. Chimeric antigen receptors (CARs) are recombinant receptors that comprise an extracellular antigen-targeting domain in conjunction with one or more intracellular T cell signaling domains that can be introduced into T cells by genetic modification to redirect their specificity to the CAR-targeted antigen. Administration of CD19-specific CAR-modified T cells that target B cell non-Hodgkin lymphomas and leukemia has been remarkably effective in recent clinical trials, energizing the field and stimulating new efforts to identify the critical parameters of CAR design and T cell engineering that are necessary for effective cancer therapy.

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A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells

Cited by 518 publications

References 35 publications

Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

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

Chimeric antigen receptor modified T cell therapy for B cell malignancies

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A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells

Cited by 518 publications

References 35 publications

Comparison of naïve and central memory derived CD8+effector cell engraftment fitness and function following adoptive transfer

Comparison of naïve and central memory derived CD8+effector cell engraftment fitness and function following adoptive transfer

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

Chimeric antigen receptor modified T cell therapy for B cell malignancies

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Product

Resources

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Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer

Comparison of naïve and central memory derived CD8⁺effector cell engraftment fitness and function following adoptive transfer